Nucleotide analogs

ABSTRACT

Disclosed herein, inter alia, are acyclic nucleotide analogs and methods of using an acyclic nucleotide analog for treating and/or ameliorating a papillomavirus infection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/854,897, filed Sep. 15, 2015, which claims the benefit of U.S.Provisional Application No. 62/050,624, filed Sep. 15, 2014, the contentof each of which is incorporated herein by reference in its entirety andfor all purposes.

FIELD

The present application is directed, inter alia, to nucleotide analogs,pharmaceutical compositions that include a disclosed nucleotide analog,and processes for their synthesis. Also included are methods of treatingdiseases and/or conditions with the disclosed nucleotide analog, aloneor in combination therapy with one or more other agents, including inparticular for the treatment of a viral infection such as that caused bya papillomavirus.

BACKGROUND OF THE INVENTION

Viruses are infectious particles that can replicate their DNA or RNAonly within host cells. Viral infections may lead to mild to severeillnesses in humans and mammals, and in some instances, can result indeath. Examples of viral infections include hepatitis B and C, smallpox,herpes simplex, cytomegalovirus, human immunodeficiency virus (HIV),influenza, adenovirus, chickenpox, BK virus, JC virus andpapillomavirus. Viral infection can lead to cancer in humans and otherspecies. Viruses known to cause cancer include human papillomavirus(HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV and EpsteinBarr virus (EBV).

Papillomaviruses are a group of non-enveloped DNA viruses, which inhumans infect keratinocytes of skin and mucous membranes including inthe anogenital area. They are known to cause skin warts, genital warts,and respiratory papillomatosis and cancer. In women, Papillomavirusescan cause precancerous cervical lesions which lead to cervicalintraepithelial neoplasia, vaginal and anal intraepithelial neoplasia,and ultimately cervical cancer.

Several species of the alpha-papillomavirus genus contain high risktypes of HPV which are more likely to lead to human cancer. Most of thecancer-causing HPV types are from the alpha-7 and alpha-9 species andinclude types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73,and 82. Cancers caused by HPV include cervical, rectal, penile, vaginaland oropharyngeal cancer. The most common cancer-causing HPV types are16 and 18. HPV-16 and -18 are reported to be the cause of 70% ofcervical cancers; and 90% of venereal warts are caused by the low riskHPV types 6 and 11. The presence of a HPV infection can be detectedusing a PAP smear and/or DNA probe testing with products such asCEREVISTA® (Hologic), COBAS® (Roche) and other commercially availableproducts. Currently available HPV DNA tests detect DNA from 14 high-riskHPV types, including HPV-16 and HPV 18. Vaccines have been developed forHPV 6, 11, 16 and 18, which may be effective if administered prior tosexual debut. However, the HPV vaccines may provide little benefit insexually active women who have already been infected with HPV.

HPV replication and viral DNA synthesis that produce mature virionsfirst takes place in the basilar layer of cervical epithelial cells andamplifies to involve the suprabasilar cells as the infection proceeds.After months or years of infection, elements of the HPV DNA episome canbecome integrated into the epithelial cell genomic DNA. The integratedelements generally include viral L1, the long control region (LCR), andthe E6 and E7 oncogenes. This results in overexpression of E6 and E7oncoproteins that over time cause the loss of cell cycle controls andprogression to cervical cancer. However, in cervical cancer cell lineswhich have integrated HPV DNA such as HeLa (HPV18), SiHa (HPV16), CaSki(HPV16) and Me180 (HPV39) productive viral replication is not occurring.Thus, studies of compounds which inhibit cell division of human cervicalcancer cell lines that contain integrated E6 and E7 do not provideknowledge about the inhibition of productive viral DNA synthesis.Additional information regarding HPV and its replication is provided inFIELDS VIROLOGY 1662-1703 (David M. Knipe, Ph.D. and Peter M. Howley, MDeds., 6th ed., Wolters Kluwer, 2013) (2001), which is herebyincorporated by reference in its entirety. There is presently noapproved antiviral treatment for a human papillomavirus infection.

One class of antiviral drugs are nucleoside or nucleotide analogs, whichinterfere with DNA or RNA replication necessary for viral growth.Examples of antiviral nucleoside analogs include RETROVIR®, ZOVIRAX®,CYTOVENE®, EPIVIR® and EMTRIVA®.

Nucleotide analogs include the acyclic nucleoside phosphonates (ANPs).Nucleotide analogs were initially designed to circumvent the firstphosphorylation of a parent nucleoside. This first phosphorylation hasbeen identified as the limiting step in the generation of the activenucleoside triphosphate. Examples of ANPs include adefovir, tenofovirand cidofovir (CDV) which are active against human infections such asHBV, HIV and CMV, respectively. ANPs are known in the art to be poorlyadsorbed from the gastrointestinal tract of mammals due to 1) theirmolecular weight and 2) the presence of a double negative charge on thephosphonate moiety. Because of their poor oral pharmacokineticproperties, ANPs have been converted to prodrugs to produce clinicallyuseful therapeutic agents. For example, tenofovir is marketed asVIREAD®; a disoproxil (diester) fumarate salt, for the treatment of HIV.Adefovir is marketed as HEPSERA®; a dipivoxil ester, for the treatmentof HBV.

Additional examples of ANP prodrugs include the phase II pradefovir andphase III GS-7340, see, Pradere, U. et al., “Synthesis of Nucleoside andPhosphonate Prodrugs”, Chemical Reviews, 2014, 114, 9154-9218 and thestructures following.

An alternate approach to increasing the oral bioavailability of ANPs hasbeen to prepare alkoxyalkyl monoesters or alkyl monoesters. See, forexample, Beadle et al., “Synthesis and Antiviral Evaluation ofAlkoxyalkyl Derivatives of9-(S)-(3-Hydroxy-2-phosphono-methoxypropyl)adenine againstCytomegalovirus”, J. Med. Chem., 2006, 49:2010-215; Painter et al.,“Evaluation ofHexadecyloxypropyl-9-R-[2-(Phosphonomethoxy)Propyl]-Adenine, CMX157, asa Potential Treatment for Human Immunodeficiency Virus Type 1 andHepatitis B Virus Infections,” Antimicrobial Agents and Chemotherapy,2007, 51:3505-3509; Valiaeva et al., “Synthesis and antiviral evaluationof alkoxyalkyl esters of acyclic purine and pyrimidine nucleosidephosphonates against HIV-1 in vitro”, Antiviral Research, 2006,72:10-19; Aldern et al., “Update and Metabolism of Cidofovir andOleyloxyethyl-cidofovir in Human Papillomavirus Positive ME-180 HumanCervical Cancer Cells” Abstract 173 Antiviral Res., 2007, 74(3):A83;Hostetler et al., “Enhanced Anti-proliferative effects of alkoxyalkylesters of cidofovir in human cervical cancer cells in vitro” Mol. CancerTher., 2006, 51(1):156-158; Trahan et al., “Anti-proliferative Effectsof Octadecyloxyethyl-Phosphonomethoxyethylguanine (ODE-PMEG) on theGrowth of Human Papilloma Virus Positive Cervical Carcinoma (ME-180)Cells in Vitro and Solid Tumors in Athymic Nude Mice” Abstract 85Antiviral Res., 2009, 82(2):A42; Valiaeva et al., “Anti-proliferativeEffects of Octadecyloxyethyl 9-[2-(Phosphonomethoxy)Ethyl]Guanineagainst Me-180 Human Cervical Cancer Cells in vitro and in vivo”,Chemotherapy, 2010, 56:(1)54-59; Valiaeva et al., “Synthesis andantiviral evaluation of 9-(S)-[3-alkoxy-2-(phosphonomethoxy)-propyl]nucleoside alkoxyalkyl esters: Inhibitors of hepatitis C virus and HIV-1replication”, Bioorganic and Medicinal Chemistry, 2011, 19:4616-4625. Inaddition, see the patent applications and patents to Hostetler: U.S.Pat. No. 6,716,825; U.S. Pat. No. 7,034,014; U.S. Pat. No. 7,094,772;U.S. Pat. No. 7,098,197; U.S. Pat. No. 7,652,001; U.S. Pat. No.7,452,898; U.S. Pat. No. 7,790,703; U.S. Pat. No. 7,687,480; U.S. Pat.No. 7,749,983; U.S. Pat. No. 7,994,143; U.S. Pat. No. 8,101,745; U.S.Pat. No. 8,008,308; U.S. Pat. No. 8,193,167; U.S. Pat. No. 8,309,565;U.S. Pat. No. 8,318,700; U.S. Pat. No. 8,846,643; U.S. Pat. No.8,710,030; U.S. Pat. No. 8,889,658, US 2015/0080344 and US 2015/0051174;The Regents of The University of California: WO 1996/39831; WO2001/039724; WO 2005/087788; WO 2006/066074; WO 2006/076015; and WO2011/130557; and the Dana Farber Cancer Institute, Inc.: WO/1998/38202.

A hexadecyloxypropyl ester of cidofovir, HDP-CDV (brincidofovir), iscurrently being developed for the treatment of adenovirus and CMVinfection in HCT recipients. The drug is currently in Phase III. See,for example, U.S. Pat. No. 9,006,218; U.S. Pat. No. 8,993,542; U.S. Pat.No. 8,962,829; U.S. Pat. No. 8,614,200; U.S. Pat. No. 8,569,321; U.S.Pat. No. 7,994,143; U.S. Pat. No. 7,749,983; U.S. Pat. No. 6,599,887;U.S. Pat. No. 6,448,392; WO 2007/130783; WO 2008/133966; WO 2009/094190;WO 2011/011519; WO 2011/011710; WO 2011/017253 and WO 2011/053812.

The synthesis of phosphonomethoxyethyl or1,3-bis(phosphonomethoxy)propan-2-yl lipophilic esters of acyclicnucleoside phosphonates, and alkyl diesters of ANPs. has been disclosedSee, Holy et al., “Structure-Antiviral Activity Relationship in theSeries of Pyrimidine and Purine N-[2-(2-Phosphono-methyloxy)ethyl]Nucleotide Analogues. Derivatives Substituted at the Carbon Atoms of thebase”, J. Med. Chem., 1999, 42(12):2064-2086; Holy et al., “Synthesis ofphosphonomethoxyethyl or 1,3-bis(phosphonomethoxy) propan-2-yllipophilic esters of acyclic nucleoside phosphonates”, Tetrahedron,2007, 63:11391-11398. The synthesis of anti-cancer phosphonate analogshas also been investigated; see, WO 2004/096235; WO 2005/066189 and WO2007/002808. The synthesis of prodrugs of ANPs has also beeninvestigated; see, WO 2006/114064 and WO 2006/114065. The synthesis ofpurine nucleoside monophosphate prodrugs for the treatment of cancer andviral infections has also been investigated; see, WO 2010/091386.

Certain acyclic nucleoside phosphonate diesters are disclosed in U.S.Pat. No. 8,835,630 (which was published on the priority date of thepresent application) and US 2014/0364397.

PMEG diphosphate is a chain-terminating inhibitor of DNA polymerasesalpha, delta and epsilon (Kramata P, Votruba I, Otová B, Holý A.Different inhibitory potencies of acyclic phosphonomethoxyalkylnucleotide analogs toward DNA polymerases alpha, delta and epsilon. MolPharmacol. 1996 June; 49(6):1005-11. PubMed PMID: 8649338). However itsinhibition of polymerases beta, gamma and epsilon is less pronounced.Pol delta and epsilon are involved in DNA repair and have exonucleaseactivity. Kramata et al have shown that PMEG-terminated primers cannotbe repaired by pol delta (Kramata P, Downey K M, Paborsky L R.Incorporation and excision of 9-(2-phosphonylmethoxyethyl)guanine (PMEG)by DNA polymerase delta and epsilon in vitro. J Biol. Chem. 1998 Aug.21; 273(34):21966-71. PubMed PMID: 9705337).

While there are currently no approved pharmaceutical drugs that are usedto treat an early HPV infection that has not yet progressed to cancer,certain epicatechins, epicatechin oligomers or thiolated epicatechinsfrom Theobroma cacao for treatment of genital warts have been disclosed;see, US 2015/0011488.

The pyrimidine, 5-fluorouracil, is active against HPV but is highlytoxic. The broad spectrum antiviral agent GSK983 has been shown to haveanti HPV activity but has not been studied extensively in humans yet.Other small molecules having anti-HPV activity include the cobaltcomplex CDC-96, indol-3-carbinol (I3C) and the immunomodulatoryImiquimod, see, US 2015/0011488.

To date, there are no approved pharmaceutical drugs that are used totreat an early HPV infection that has not yet progressed to cancer.Provided herein are solutions to these and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

In one embodiment, the invention describes compounds with antiviralactivity against a papillomavirus in the absence of a significantantiproliferative host cell effect.

Therefore, the invention includes antiviral agents that selectivelyinhibit and/or block viral DNA synthesis and/or the production ofvirions of high risk HPV types. Inhibition and/or blockage of viral DNAsynthesis and/or the production of virions of high risk HPV types canthen eradicate the papillomavirus infection before cellular changes takeplace which can lead to invasive cancers, such as those describedherein, and thus represent an advance in the art.

One embodiment of the invention provides an effective amount of anantiviral compound of Formula (I), or a pharmaceutically acceptable saltthereof, for ameliorating or treating a host infected with a humanpapillomavirus, wherein the human papillomavirus can be ameliorated ortreated by inhibiting viral replication by inhibiting the synthesis ofviral DNA. Another embodiment disclosed herein is a method forameliorating or treating a host infected with a human papillomavirusthat includes contacting a cell infected with the human papillomavirusand/or administering to a subject infected with the human papillomavirusan effective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein the human papillomavirus can beameliorated or treated by selectively inhibiting viral replication byinhibiting the synthesis of viral DNA.

The present invention includes at least the following features:

(a) an antiviral compound of Formula I as described herein, andpharmaceutically acceptable salts and prodrugs thereof (each of whichand all subgenuses and species thereof considered individually andspecifically described);

(b) an antiviral Formula I as described herein, and pharmaceuticallyacceptable salts and prodrugs thereof, for use in treating or preventinga viral infection such as papillomavirus;

(c) use of Formula I, and pharmaceutically acceptable salts and prodrugsthereof in the manufacture of a medicament for use in treating orpreventing a viral disease such as papillomavirus;

(d) a process for manufacturing a medicament intended for thetherapeutic use for treating or preventing treating or preventing aviral disease such as papillomavirus further herein characterized inthat Formula I as described herein is used in the manufacture;

(e) a pharmaceutical formulation comprising an effective host-treatingamount of the Formula I or a pharmaceutically acceptable salt or prodrugthereof together with a pharmaceutically acceptable carrier or diluent;

(f) Formula I as described herein in substantially pure form, includingsubstantially isolated from other chemical entities (e.g., at least 90or 95%);

(g) processes for the manufacture of the compounds of Formula I andsalts, compositions, dosage forms thereof; and

(h) processes for the preparation of therapeutic products that containan effective amount of Formula I, as described herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

As used herein, any “R” group(s) such as, without limitation, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and represent substituents that can beattached to the indicated atom. An R group may be substituted orunsubstituted. If two “R” groups are described as being “taken together”the R groups and the atoms they are attached to can form a cycloalkyl,cycloalkenyl, aryl, heteroaryl or heterocycle. For example, withoutlimitation, if R^(a) and R^(b) of an NR^(a)R^(b) group are indicated tobe “taken together,” it means that they are covalently bonded to oneanother to form a ring:

In addition, if two “R” groups are described as being “taken together”with the atom(s) to which they are attached to form a ring as analternative, the R groups are not limited to the variables orsubstituents defined previously.

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent(s) may beselected from one or more of the indicated substituents. If nosubstituents are indicated, it is meant that the indicated “optionallysubstituted” or “substituted” group may be substituted with one or moregroup(s) individually and independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl,aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy,acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl,haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, an amino, a mono-substituted amino group anda di-substituted amino group.

As used herein, “C_(a) to C_(b),” “C_(a)-C_(b),” “C_(a-b)” and the likein which “a” and “b” are integers, refer to the number of carbon atomsin an alkyl, alkenyl or alkynyl group, or the number of carbon atoms inthe ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclylgroup. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl,ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl orring of the heterocyclyl can contain from “a” to “b”, inclusive, carbonatoms. Thus, for example, a “C₁ to C₄ alkyl” group refers to all alkylgroups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—,(CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—. If no “a” and “b”are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkylcycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest rangedescribed in these definitions is to be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl andhexyl. The alkyl group may be substituted or unsubstituted.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds. Analkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more triple bonds. Analkynyl group may be unsubstituted or substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein). Whencomposed of two or more rings, the rings may be connected together in afused fashion. A cycloalkenyl group may be unsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group.Examples of aryl groups include, but are not limited to, benzene,naphthalene and azulene. An aryl group may be substituted orunsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one or more heteroatoms, that is, an elementother than carbon, including but not limited to, nitrogen, oxygen andsulfur. The number of atoms in the ring(s) of a heteroaryl group canvary. For example, the heteroaryl group can contain 4 to 14 atoms in thering(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).Furthermore, the term “heteroaryl” includes fused ring systems where tworings, such as at least one aryl ring and at least one heteroaryl ring,or at least two heteroaryl rings, share at least one chemical bond.Examples of heteroaryl rings include, but are not limited to, furan,furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole,benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole,benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole,benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine,pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnolineand triazine. A heteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatom(s) is anelement other than carbon including, but not limited to, oxygen, sulfurand nitrogen. A heterocycle may further contain one or more carbonyl orthiocarbonyl functionalities, so as to make the definition includeoxo-systems and thio-systems such as lactams, lactones, cyclic imides,cyclic thioimides and cyclic carbamates. When composed of two or morerings, the rings may be joined together in a fused fashion.Additionally, any nitrogens in a heterocyclyl or a heteroalicyclyl maybe quaternized. Heterocyclyl or heteroalicyclic groups may beunsubstituted or substituted. Examples of such “heterocyclyl” or“heteroalicyclyl” groups include but are not limited to, 1,3-dioxin,1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane,1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole,1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, trioxane,hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline,isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline,thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine,piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone,pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran,tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide,thiamorpholine sulfone and their benzo-fused analogs (e.g.,benzimidazolidinone, tetrahydroquinoline and 3,4-methylenedioxyphenyl).

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl groupconnected, as a substituent, via a lower alkylene group. The loweralkylene and aryl group of an aryl(alkyl) may be substituted orunsubstituted. Examples include but are not limited to benzyl,2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to aheteroaryl group connected, as a substituent, via a lower alkylenegroup. The lower alkylene and heteroaryl group of heteroaryl(alkyl) maybe substituted or unsubstituted. Examples include but are not limited to2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl),pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl),and their benzo-fused analogs.

A “(heteroalicyclyl)alkyl” and “(heterocyclyl)alkyl” refer to aheterocyclic or a heteroalicyclylic group connected, as a substituent,via a lower alkylene group. The lower alkylene and heterocyclyl of a(heteroalicyclyl)alkyl may be substituted or unsubstituted. Examplesinclude but are not limited tetrahydro-2H-pyran-4-yl(methyl),piperidin-4-yl(ethyl), piperidin-4-yl(propyl),tetrahydro-2H-thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl).

“Lower alkylene groups” are straight-chained —CH₂— tethering groups,forming bonds to connect molecular fragments via their terminal carbonatoms. Examples include but are not limited to methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—) and butylene(—CH₂CH₂CH₂CH₂—). A lower alkylene group can be substituted by replacingone or more hydrogen of the lower alkylene group with a substituent(s)listed under the definition of “substituted.”

As used herein, “alkoxy” refers to the formula —OR wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or(heterocyclyl)alkyl is defined herein. A non-limiting list of alkoxysare methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, benzyloxy, hexadecyloxyand octadecyloxy. An alkoxy may be substituted or unsubstituted.

As used herein, “acyl” refers to a hydrogen an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, heteroaryl(alkyl) or heterocyclyl(alkyl)connected, as substituents, via a carbonyl group. Examples includeformyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may besubstituted or unsubstituted.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkylmay be substituted or unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include butare not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. Asulfenyl may be substituted or unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to sulfenyl. A sulfinyl may be substitutedor unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to sulfenyl. A sulfonyl may be substituted orunsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or(heterocyclyl)alkyl, as defined herein. An O-carboxy may be substitutedor unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or unsubstituted.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or unsubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group whereineach X is a halogen.

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R^(A))—”group wherein each X is a halogen, and R^(A) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl.

The term “amino” as used herein refers to a “—NH₂” group.

As used herein, the term “hydroxy” refers to a “—OH” group.

A “cyano” group refers to a “—CN” group.

The term “azido” as used herein refers to a “—N₃” group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “mercapto” group refers to an “—SH” group.

A “carbonyl” group refers to a “C═O” group.

An “S-sulfonamido” group refers to a “—SO₂N(R^(A)R^(B))” group in whichR^(A) and R^(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An S-sulfonamido may besubstituted or unsubstituted.

An “N-sulfonamido” group refers to a “RSO₂N(R^(A))—” group in which Rand R^(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-sulfonamido may besubstituted or unsubstituted.

An “O-carbamyl” group refers to a “—OC(═O)N(R^(A)R^(B))” group in whichR^(A) and R^(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An O-carbamyl may besubstituted or unsubstituted.

An “N-carbamyl” group refers to an “ROC(═O)N(R^(A))—” group in which Rand R^(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-carbamyl may besubstituted or unsubstituted.

An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R^(A)R^(B))” group inwhich R^(A) and R^(B) can be independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl,aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. An O-thiocarbamyl maybe substituted or unsubstituted.

An “N-thiocarbamyl” group refers to an “ROC(═S)N(R^(A))—” group in whichR and R^(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-thiocarbamyl may besubstituted or unsubstituted.

A “C-amido” group refers to a “—C(═O)N(R^(A)R^(B))” group in which R^(A)and R^(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. A C-amido may be substitutedor unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R^(A))—” group in which R andR^(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-amido may be substitutedor unsubstituted.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine and iodine.

Where the numbers of substituents is not specified (e.g. haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two or three atoms.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

As used herein, the term “phosphonate” is used in its ordinary sense asunderstood by those skilled in the art, and includes its protonatedforms (for example,

As used herein, the terms “monophosphonate” and “diphosphonate” are usedin their ordinary sense as understood by those skilled in the art, andinclude protonated forms. Additionally, the term “phosphate” is used inits ordinary sense as understood by those skilled in the art, andincludes its protonated forms (for example,

The terms “monophosphate,” “diphosphate,” and “triphosphate” are alsoused in their ordinary sense as understood by those skilled in the art,and include protonated forms.

The terms “protecting group” and “protecting groups” as used hereinrefer to any atom or group of atoms that is added to a molecule in orderto prevent existing groups in the molecule from undergoing unwantedchemical reactions. Examples of protecting group moieties are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmie,Protective Groups in Organic Chemistry Plenum Press, 1973, both of whichare hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g.,t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls andarylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether(e.g. methoxymethyl ether); substituted ethyl ether; a substitutedbenzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,tri-iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl ort-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g.methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclicketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane,1,3-dioxolanes and those described herein); acyclic acetal; cyclicacetal (e.g., those described herein); acyclic hemiacetal; cyclichemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane);orthoesters (e.g., those described herein) and triarylmethyl groups(e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr);4,4′,4″-trimethoxytrityl (TMTr); and those described herein).

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic, acetic, succinic, lactic, malic,tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic,p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceuticalsalts can also be obtained by reacting a compound with a base to form asalt such as an ammonium salt, an alkali metal salt, such as a sodium ora potassium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine,cyclohexylamine, triethanolamine, ethylenediamine, and salts with aminoacids such as arginine and lysine.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least,’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction, but instead as merely intended to highlight alternative oradditional features that may or may not be utilized in a particularembodiment. In addition, the term “comprising” is to be interpretedsynonymously with the phrases “having at least” or “including at least”.When used in the context of a process, the term “comprising” means thatthe process includes at least the recited steps, but may includeadditional steps. When used in the context of a compound, composition ordevice, the term “comprising” means that the compound, composition ordevice includes at least the recited features or components, but mayalso include additional features or components. Likewise, a group ofitems linked with the conjunction ‘and’ should not be read as requiringthat each and every one of those items be present in the grouping, butrather should be read as ‘and/or’ unless expressly stated otherwise.Similarly, a group of items linked with the conjunction ‘or’ should notbe read as requiring mutual exclusivity among that group, but rathershould be read as ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single claim element may fulfill the functions of severalitems recited in the claims. The mere fact that certain measures arerecited in mutually different dependent claims does not indicate that acombination of these measures cannot be used to advantage. Any referencesigns in the claims should not be construed as limiting the scope.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included. For example alltautomers of phosphonates and heterocyclic bases known in the art areintended to be included, including tautomers of natural and non-naturalpurine-bases and pyrimidine-bases are intended to be included.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates and hydrates. Inembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

As used herein, a “subject” refers to an animal that is a host for aviral infection as described herein. “Animal” includes a mammal.“Mammals” includes, without limitation, mice, rats, rabbits, guineapigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys,chimpanzees, and apes, and, in particular, humans. In a typicalembodiment, the subject is human.

As used herein, the terms “treating,” “treatment,” “therapeutic,” or“therapy” do not necessarily mean total cure or abolition of the diseaseor condition. Any alleviation of any undesired signs or symptoms of adisease or condition, to any extent can be considered treatment and/ortherapy. Furthermore, treatment may include acts that may worsen thepatient's overall feeling of well-being or appearance.

The terms “therapeutically effective amount” and “effective amount” areused to indicate an amount of an active compound, or pharmaceuticalagent, that elicits the biological or medicinal response indicated. Forexample, an effective amount of compound can be the amount needed toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated This response may occur in atissue, system, animal or human and includes alleviation of the signs orsymptoms of the disease being treated. Determination of an effectiveamount is well within the capability of those skilled in the art, inview of the disclosure provided herein. The effective amount of thecompounds disclosed herein required as a dose will depend on the routeof administration, the type of animal, including human, being treated,and the physical characteristics of the specific animal underconsideration. The dose can be tailored to achieve a desired effect, butwill depend on such factors as weight, diet, concurrent medication andother factors which those skilled in the medical arts will recognize.

Some embodiments disclosed herein relate to the use of an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, in the preparation of a medicine for ameliorating ortreating a host infected with a human papillomavirus, wherein the humanpapillomavirus can be ameliorated or treated by inhibiting viralreplication by inhibiting the synthesis of viral DNA. Other embodimentsdisclosed herein relate to the use of an effective amount of a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, forameliorating or treating a host infected with a human papillomavirus,wherein the human papillomavirus can be ameliorated or treated byinhibiting viral replication by inhibiting the synthesis of viral DNA.Embodiments disclosed herein relate to a method for ameliorating ortreating a host infected with a human papillomavirus that can includecontacting a cell infected with the human papillomavirus in a subjectinfected with the human papillomavirus an effective amount of a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, whereinthe human papillomavirus can be ameliorated or treated by inhibitingviral replication by inhibiting the synthesis of viral DNA. Embodimentsdisclosed herein relate to a method for ameliorating or treating a hostinfected with a human papillomavirus that can include administering to asubject infected with the human papillomavirus an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,wherein the human papillomavirus can be ameliorated or treated byinhibiting viral replication by inhibiting the synthesis of viral DNA.Some embodiments disclosed herein relate a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in ameliorating ortreating a host infected with a human papillomavirus, wherein the humanpapillomavirus can be ameliorated or treated by inhibiting viralreplication by inhibiting the synthesis of viral DNA.

In embodiments, the human papillomavirus can be a high-risk humanpapillomavirus, such as those described herein. For example, thehigh-risk human papillomavirus can be selected from HPV-16, HPV-18,HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58,HPV-59, HPV-68, HPV-73 and HPV-82. In embodiments, the humanpapillomavirus can be HPV-16. In embodiments, the human papillomaviruscan be HPV-18. In embodiments, the human papillomavirus can be one ormore of the following high-risk types: HPV-31, HPV-33, HPV-35, HPV-39,HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73 andHPV-82. As described herein, the presence of a HPV infection can bedetected using a PAP smear and/or DNA probe testing (for example, HPVDNA probe testing for one or more high-risk HPV types). Therefore, Inembodiments, an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be provided to a subjectdiagnosed with a HPV infection, for example a high-risk HPV infection,by a DNA test, such as one of the HPV DNA tests described herein.

In embodiments, the human papillomavirus can be a low-risk humanpapillomavirus, including those described herein. In embodiments, thehuman papillomavirus can be HPV-6. In embodiments, the humanpapillomavirus can be HPV-11.

A compound of Formula (I), or a pharmaceutically acceptable saltthereof, can be used to ameliorate and/or treat a host infected with oneor more types of human papillomaviruses. For example, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, can be usedto ameliorate and/or treat HPV-16 and HPV-18. In embodiments, a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, can beused to ameliorate and/or treat both high-risk and low-risk HPV.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight, the severity of theaffliction, and mammalian species treated, the particular compoundsemployed, and the specific use for which these compounds are employed.The determination of effective dosage levels, that is the dosage levelsnecessary to achieve the desired result, can be accomplished by oneskilled in the art using routine methods, for example, human clinicaltrials and in vitro studies.

The dosage may range broadly, depending upon the desired effects and thetherapeutic indication. Alternatively dosages may be based andcalculated upon the surface area of the patient, as understood by thoseof skill in the art. Although the exact dosage will be determined on adrug-by-drug basis, in most cases, some generalizations regarding thedosage can be made. The daily dosage regimen for an adult human patientmay be, for example, an oral dose of between 0.01 mg and 3000 mg of eachactive ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.For a topical or intravaginal administration, the dose may be between0.02 mg to 200 mg. The dosage may be a single one or a series of two ormore given in the course of one or more days, as is needed by thesubject. In embodiments, the compounds will be administered for a periodof continuous therapy, for example for a week or more, or for months oryears. In embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be administered less frequently compared tothe frequency of administration of another agent. In embodiments, thetotal time of the treatment regime with a compound of Formula (I), or apharmaceutically acceptable salt thereof, can less compared to the totaltime of the treatment regime with another agent.

In instances where human dosages for compounds have been established forat least some condition, those same dosages may be used, or dosages thatare between about 0.1% and 500%, more preferably between about 25% and250% of the established human dosage. Where no human dosage isestablished, as will be the case for newly-discovered pharmaceuticalcompositions, a suitable human dosage can be inferred from ED₅₀ or ID₅₀values, or other appropriate values derived from in vitro or in vivostudies, as qualified by toxicity studies and efficacy studies inanimals.

In cases of administration of a pharmaceutically acceptable salt,dosages may be calculated as the free base. As will be understood bythose of skill in the art, in certain situations it may be necessary toadminister the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order toeffectively and aggressively treat particularly aggressive diseases orinfections.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations. Dosageintervals can also be determined using MEC value. Compositions should beadministered using a regimen which maintains plasma levels above the MECfor 10-90% of the time, preferably between 30-90% and most preferablybetween 50-90%. In cases of local administration or selective uptake,the effective local concentration of the drug may not be related toplasma concentration.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the condition to be treated and to the route ofadministration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and preferably human, cell line. Theresults of such studies are often predictive of toxicity in animals,such as mammals, or more specifically, humans. Alternatively, thetoxicity of particular compounds in an animal model, such as mice, rats,rabbits, or monkeys, may be determined using known methods. The efficacyof a particular compound may be established using several recognizedmethods, such as in vitro methods, animal models, or human clinicaltrials. When selecting a model to determine efficacy, the skilledartisan can be guided by the state of the art to choose an appropriatemodel, dose, route of administration and/or regime.

As described herein, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can have a moiety(ies) that neutralize thecharge of the phosphonate. By neutralizing the charge on thephosphonate, penetration of the cell membrane may be facilitated as aresult of the increased lipophilicity of the compound. Once absorbed andtaken inside the cell, the groups attached to the phosphorus can beeasily removed by esterases, proteases and/or other enzymes. Inembodiments, the groups attached to the phosphorus can be removed bysimple hydrolysis. Inside the cell, the phosphonate thus released maythen be metabolized by cellular enzymes to the monophosphate or to thediphosphate, the active metabolite. Furthermore, In embodiments, varyingthe substituents on a compound described herein, such as a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, can helpmaintain the efficacy of the compound by reducing undesirable effects,such as isomerization.

In embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can act as a chain terminator of DNA synthesis.Once the compound is incorporated into a DNA chain, no furtherelongation is observed to occur. In embodiments, a compound of Formula(I) or a pharmaceutically acceptable salt thereof, is metabolized suchthat the groups attached to the phosphorus atom are removed to generatea phosphonic acid. The phosphonic acid can then be anabolized to adiphosphate, the active metabolite, that can act as a chain terminatorof DNA synthesis. Once the compound is incorporated into a DNA chain, nofurther elongation is observed to occur.

Additionally, In embodiments, the presence of a moiety(ies) thatneutralizes the charge of the phosphonate can increase the stability ofthe compound by inhibiting its degradation. Also, In embodiments, thepresence of a moiety(ies) that neutralizes the charge of the phosphonatecan make the compound more resistant to cleavage in vivo and providesustained, extended efficacy. In embodiments, a moiety(ies) thatneutralizes the charge of the phosphonate can facilitate the penetrationof the cell membrane by a compound of Formula (I) by making the compoundmore lipophilic. In embodiments, a moiety(ies) that neutralizes thecharge of the phosphonate can have improved oral bioavailability,improved aqueous stability and/or reduced risk of byproduct-relatedtoxicity.

Compounds

In embodiments disclosed herein, there is provided use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof:

wherein: B¹ can be

Z¹ and Z² can be independently —O— (oxygen) or —NR^(Z)—, wherein R^(Z)can be H (hydrogen) or an optionally substituted C₁₋₄ alkyl; R¹ can beselected from absent, H (hydrogen), an optionally substituted —C₁₋₂₄alkyl, an optionally substituted —C₂₋₂₄ alkenyl, an optionallysubstituted —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionally substituted—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted aryl, anoptionally substituted aryl(C₁₋₄ alkyl), an optionally substitutedheteroaryl, an optionally substituted heterocyclyl,

R² can be selected from an optionally substituted —C₁₋₂₄ alkyl, anoptionally substituted —C₂₋₂₄ alkenyl, an optionally substituted—(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionally substituted —(CHR⁴)_(b)—O—C₂₋₂₄alkenyl, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl),

or Z¹ and Z² can be—O—; and R¹ and R² can be taken together to form a moiety selected froman optionally substituted

and an optionally substituted

wherein Z¹, Z², and R², the phosphorus and the moiety form asix-membered to ten-membered ring system; R³ can be an unsubstitutedC₁₋₆ alkyl or an unsubstituted C₃₋₆ cycloalkyl; each R⁴ can beindependently H (hydrogen), —(CH₂)_(c)—S—C₁₋₂₄ alkyl or—O—(CH₂)_(d)—R^(4A); each R^(4A) can be H (hydrogen), an optionallysubstituted C₁₋₂₄ alkyl or an optionally substituted aryl; each R⁵, eachR⁶ and each R⁸ can be independently an optionally substituted C₁₋₈alkyl, an optionally substituted C₂₋₈ alkenyl, an optionally substitutedcycloalkyl or an optionally substituted aryl; each R⁹ can beindependently H (hydrogen) or an optionally substituted C₁₋₆ alkyl; eachR¹⁰ is independently selected from the group consisting of H, anunsubstituted C₁₋₆ alkyl, —CH₂SH,—CH₂CH₂(C═O)NH₂, —CH₂CH₂SCH₃, CH₂— an optionally substituted phenyl,—CH₂OH, —CH(OH)CH₃,

—CH₂(C═O)OH, —CH₂CH₂(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; each R¹¹ can be independently H (hydrogen), anoptionally substituted C₁₋₈ alkyl, an optionally substituted cycloalkyl,an optionally substituted aryl or an optionally substituted aryl(C₁₋₆alkyl); each a and each b can be independently 1, 2, 3 or 4; each c andeach d can be independently 0, 1, 2 or 3; and provided that when R¹ isabsent, then Z¹ is —O—.

In embodiments, R¹ can be absent or H; and R² can be selected from anoptionally substituted —C₁₋₂₄ alkyl, an optionally substituted —C₂₋₂₄alkenyl, an optionally substituted —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, anoptionally substituted —(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl),

In other embodiments, R¹ and R² can be independently selected from anoptionally substituted —C₁₋₂₄ alkyl, an optionally substituted —C₂₋₂₄alkenyl, an optionally substituted —(CHR⁴)_(b)—O—C₁₋₂₄ alkyl, anoptionally substituted —(CHR⁴)_(a)—O—C₂₋₂₄ alkenyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl),

Some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, are provided in Table 1.

In Table 1,

TABLE 1 B¹ Z¹ Z² R¹ R² G1 O O absent or H —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl G1 OO absent or H —(CHR⁴)_(a)—O—C₁₂₋₂₄ alkyl G1 O O —(CHR⁴)_(a)—O—C₁₋₂₄alkyl —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl G1 O O —(CHR⁴)_(a)—O—C₁₂₋₂₄ alkyl—(CHR⁴)_(a)—O—C₁₂₋₂₄ alkyl G1 O O absent or H —(CH₂)₂—O—(CH₂)₁₇CH₃ G1 OO absent or H —(CH₂)₃—O—(CH₂)₁₅CH₃ G1 O O —(CH₂)₂—O—(CH₂)₁₇CH₃—(CH₂)₂—O—(CH₂)₁₇CH₃ G1 O O —(CH₂)₃—O—(CH₂)₁₅CH₃ —(CH₂)₃—O—(CH₂)₁₅CH₃ G1O O absent or H 1-O-octadecyl-2-O-benzyl-sn- glyceryl G1 O O absent or H—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl G1 O O absent or H —(CHR⁴)_(b)—O—C₂₋₂₄alkenyl G1 O O —(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl —(CHR⁴)_(b)—O—C₂₋₂₄ alkenylG1 O O —(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl —(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl G1 O Oabsent or H —C₁₋₂₄ alkyl G1 O O absent or H —C₁₂₋₂₄ alkyl G1 O O absentor H —C₂₋₂₄ alkenyl G1 O O absent or H —C₁₂₋₂₄ alkenyl G1 O O —C₁₋₂₄alkyl —C₁₋₂₄ alkyl G1 O O —C₁₂₋₂₄ alkyl —C₁₂₋₂₄ alkyl G1 O O —C₂₋₂₄alkenyl —C₂₋₂₄ alkenyl G1 O O —C₁₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G1 O Oabsent or H aryl G1 O O absent or H phenyl G1 O O aryl aryl G1 O Ophenyl phenyl G1 O O absent or H aryl(C₁₋₄ alkyl) G1 O O absent or Hbenzyl G1 O O aryl(C₁₋₄ alkyl) aryl(C₁₋₄ alkyl) G1 O O benzyl benzyl G1O O absent or H

G1 O O absent or H

G1 O O

G1 O O

G1 O O absent or H

G1 O O absent or H

G1 O O

G1 O O

G1 O O absent or H

G1 O O

G1 NCH₃ O —(CH₂)₃CH₂Cl

G1 ++ O —(CH₂)₃CH₂Cl

G1 O NH absent or H

G1 NH NH

G1 O NH aryl

G1 O O

G1 O O

G2 O O absent or H —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl G2 O O absent or H—(CHR⁴)_(a)—O—C₁₂₋₂₄ alkyl G2 O O —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl—(CHR⁴)_(a)—O—C₁₋₂₄ alkyl G2 O O —(CHR⁴)_(a)—O—C₁₂₋₂₄ alkyl—(CHR⁴)_(a)—O—C₁₂₋₂₄ alkyl G2 O O absent or H —(CH₂)₂—O—(CH₂)₁₇CH₃ G2 OO absent or H —(CH₂)₃—O—(CH₂)₁₅CH₃ G2 O O —(CH₂)₂—O—(CH₂)₁₇CH₃—(CH₂)₂—O—(CH₂)₁₇CH₃ G2 O O —(CH₂)₃—O—(CH₂)₁₅CH₃ —(CH₂)₃—O—(CH₂)₁₅CH₃ G2O O absent or H 1-O-octadecyl-2-O-benzyl-sn- glyceryl G2 O O absent or H—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl G2 O O absent or H —(CHR⁴)_(b)—O—C₂₋₂₄alkenyl G2 O O —(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl —(CHR⁴)_(b)—O—C₂₋₂₄ alkenylG2 O O —(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl —(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl G2 O Oabsent or H —C₁₋₂₄ alkyl G2 O O absent or H —C₁₂₋₂₄ alkyl G2 O O absentor H —C₂₋₂₄ alkenyl G2 O O absent or H —C₁₂₋₂₄ alkenyl G2 O O —C₁₋₂₄alkyl —C₁₋₂₄ alkyl G2 O O —C₁₂₋₂₄ alkyl —C₁₂₋₂₄ alkyl G2 O O —C₂₋₂₄alkenyl —C₂₋₂₄ alkenyl G2 O O —C₁₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G2 O Oabsent or H aryl G2 O O absent or H phenyl G2 O O aryl aryl G2 O Ophenyl phenyl G2 O O absent or H aryl(C₁₋₄ alkyl) G2 O O absent or Hbenzyl G2 O O aryl(C₁₋₄ alkyl) aryl(C₁₋₄ alkyl) G2 O O benzyl benzyl G2O O absent or H

G2 O O absent or H

G2 O O

G2 O O

G2 O O absent or H

G2 O O absent or H

G2 O O

G2 O O

G2 O O absent or H

G2 O O

G2 NCH₃ O —(CH₂)₃CH₂Cl

G2 ++ O —(CH₂)₃CH₂Cl

G2 O NH absent or H

G2 NH NH

G2 O NH aryl

G2 O O

G2 O O

++ = N(CH₂)—CH(OH)—CH₂OH

In Table 1, —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, —(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, aryl(including phenyl), aryl(C₁₋₄ alkyl) (including benzyl),

can be each optionally substituted. Those skilled in the art understandthat when R¹ is absent, the Z¹ oxygen will have an associated negativecharge.

In embodiments, at least one of R¹ and R² can be an optionallysubstituted C₁₋₂₄ alkyl or an optionally substituted C₂₋₂₄ alkenyl. Inembodiments, R¹ and R² both can be an optionally substituted C₁₋₂₄alkyl. In embodiments, R¹ and R² both can be an optionally substitutedC₂₋₂₄ alkenyl. When one or both of R¹ and R² is an optionallysubstituted C₁₋₂₄ alkyl or an optionally substituted C₂₋₂₄ alkenyl, theoptionally substituted C₁₋₂₄ alkyl and/or the optionally substitutedC₂₋₂₄ alkenyl can be the aliphatic chain from a fatty acid. Fatty acidaliphatic chains differ by length. Types of fatty acids includeshort-chain fatty acids (fewer than six carbons), medium-chain fattyacids (six to twelve carbons), long-chain fatty acids (thirteen totwenty-one carbons), and very long-chain fatty acids (more thantwenty-two carbons). Examples of aliphatic chains include, but are notlimited to, the following: myristoleyl, myristyl, palmitoleyl, palmityl,sapienyl, oleyl, elaidyl, vaccenyl, linoleyl, α-linolenyl, arachidonyl,eicosapentaenyl, erucyl, docosahexaenyl, caprylyl, capryl, lauryl,stearyl, arachidyl, behenyl, lignoceryl and cerotyl. In embodiments, atleast one of Z¹ and Z² can be —O—. In embodiments, both Z¹ and Z² can be—O—.

In embodiments, at least one of R¹ and R² can be —(CHR⁴)_(a)—O—C₁₋₂₄alkyl. In embodiments, R¹ and R² both can be —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl.In embodiments, each R⁴ can be hydrogen. In embodiments, at least one R⁴can be —(CH₂)_(c)—S—C₁₋₂₄ alkyl. In embodiments, at least one R⁴ can be—O—(CH₂)_(d)—R^(4A). In embodiments, a can be 1. In embodiments, a canbe 2. In embodiments, a can be 3. In embodiments, a can be 4. Inembodiments, at least one of Z¹ and Z² can be —O—. In embodiments, bothZ¹ and Z² can be —O—.

In embodiments, at least one of R¹ and R² can be —(CHR⁴)_(b)—O—C₂₋₂₄alkenyl. In embodiments, R¹ and R² both can be —(CHR⁴)_(b)—O—C₂₋₂₄alkenyl. In embodiments, each R⁴ can be hydrogen. In embodiments, atleast one R⁴ can be —(CH₂)_(c)—S—C₁₋₂₄ alkyl. In embodiments, at leastone R⁴ can be —O—(CH₂)_(d)—R^(4A). In embodiments, b can be 1. Inembodiments, b can be 2. In embodiments, b can be 3. In embodiments, bcan be 4. In embodiments, at least one of Z¹ and Z² can be —O—. Inembodiments, both Z¹ and Z² can be —O—.

When an R⁴ moiety is present, in embodiments R^(4A) can be H (hydrogen).In embodiments, R^(4A) can be an optionally substituted C₁₋₂₄ alkyl. Inembodiments, R^(4A) can be an optionally substituted aryl. Inembodiments, at least one R⁴ can be —(CH₂)_(c)—S—C₁₋₂₄ alkyl, and c canbe 0. In embodiments, at least one R⁴ can be —(CH₂)_(c)—S—C₁₋₂₄ alkyl,and c can be 1. In embodiments, at least one R⁴ can be—(CH₂)_(c)—S—C₁₋₂₄ alkyl, and c can be 2. In embodiments, at least oneR⁴ can be —(CH₂)_(c)—S—C₁₋₂₄ alkyl, and c can be 3. In embodiments, atleast one R⁴ can be —O—(CH₂)_(d)—R^(4A), and d can be 0. In embodiments,at least one R⁴ can be —O—(CH₂)_(d)—R^(4A), and d can be 1. Inembodiments, at least one R⁴ can be —O—(CH₂)_(d)—R^(4A), and d can be 2.In embodiments, at least one R⁴ can be —O—(CH₂)_(d)—R^(4A), and d can be3. In embodiments, at least one of R¹ and R² can be1-O-octadecyl-2-O-benzyl-sn glyceryl. When more than one R⁴ is present,the R⁴ moieties can be the same, or at least one R⁴ can be different.

In embodiments, at least one of R¹ and R² can be an optionallysubstituted aryl. In embodiments, R¹ and R² both can be an optionallysubstituted aryl. For example, one or both R¹ and R² can be anoptionally substituted phenyl. In embodiments, at least one of R¹ and R²can be an optionally substituted aryl(C₁₋₄ alkyl). In embodiments, R¹and R² both can be an optionally substituted aryl(C₁₋₄ alkyl). Asuitable optionally substituted aryl(C₁₋₄ alkyl) is an optionallysubstituted benzyl. When the aryl and/or aryl(C₁₋₄ alkyl) issubstituted, the aryl ring can be substituted with 1, 2, 3 or more than3 substituents. When more than two substituents are present, thesubstituents can be the same or different. In embodiments, the aryl ringcan be a para-, ortho- or meta-substituted phenyl. In embodiments, atleast one of Z¹ and Z² can be —O—. In embodiments, both Z¹ and Z² can be—O—.

In embodiments, at least one of R¹ and R² can be

In embodiments, R¹ and R² both can be

In embodiments, R¹ and R² both can be

In embodiments, R⁵ can be an optionally substituted C₁₋₈ alkyl. Inembodiments, R⁵ can be an unsubstituted C₁₋₆ alkyl. In embodiments, R⁵can be an optionally substituted C₂₋₈ alkenyl, such as an optionallysubstituted allyl. In embodiments, R⁵ can be an optionally substitutedcycloalkyl, for example, an optionally substituted C₃₋₆ cycloalkyl or anoptionally substituted C₅₋₆ cycloalkyl. In embodiments, R⁵ can be anoptionally substituted aryl, such as an optionally substituted phenyl.In embodiments, R⁶ can be an optionally substituted C₁₋₈ alkyl. Inembodiments, R⁶ can be an unsubstituted C₁₋₆ alkyl. In embodiments, R⁶can be an optionally substituted C₂₋₈ alkenyl. In embodiments, R⁶ can bean optionally substituted cycloalkyl. In embodiments, R⁶ can be anoptionally substituted aryl, such as an optionally substituted phenyl.Examples of suitable R⁶ groups include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, pentyl(branched or straight chained), hexyl (branched or straight chained), anoptionally substituted allyl, an optionally substituted C₃₋₆ cycloalkyl,an optionally substituted C₅₋₆ cycloalkyl and an optionally substitutedphenyl. In embodiments, at least one of Z¹ and Z² can be —O—. Inembodiments, both Z¹ and Z² can be —O—. In embodiments, one or both ofR¹ and R² can be isopropyloxycarbonyloxymethyl (POC). In embodiments, R¹and R² both can be a isopropyloxycarbonyloxymethyl (POC) group, and forma bis(isopropyloxycarbonyloxymethyl) (bis(POC)) prodrug. In embodiments,one or both of R¹ and R² can be pivaloyloxymethyl (POM). In embodiments,R¹ and R² both can be a pivaloyloxymethyl (POM) group, and form abis(pivaloyloxymethyl) (bis(POM)) prodrug.

In embodiments, at least one of R¹ and R² can be

In embodiments, R¹ and R² both can be

In embodiments, R¹ and R² both can be

In embodiments, R⁸ can be an optionally substituted C₁₋₈ alkyl. Inembodiments, R⁸ can be an unsubstituted C₁₋₆ alkyl. In embodiments, R⁸can be an optionally substituted C₂₋₈ alkenyl, such as an optionallysubstituted allyl. In embodiments, R⁸ can be an optionally substitutedcycloalkyl, for example, an optionally substituted C₃₋₆ cycloalkyl or anoptionally substituted C₅₋₆ cycloalkyl. In embodiments, R⁸ can be anoptionally substituted aryl, such as an optionally substituted phenyl.In embodiments, at least one of Z¹ and Z² can be —O—. In embodiments,both Z¹ and Z² can be —O—. In embodiments, R and R² both can be aS-acylthioethyl (SATE) group and form a SATE ester prodrug. Inembodiments, R¹ and R² both can be aS-[(2-hydroxyethyl)sulfidyl]-2-thioethyl (DTE) group and form a DTEester prodrug. In embodiments, one of R¹ and R² can be a S-acylthioethyl(SATE) group, and the other of R¹ and R² can be an optionallysubstituted phenyl group and form a phenyl(SATE) prodrug. Inembodiments, one of R¹ and R² can be a S-acylthioethyl (SATE) group, andthe other of R¹ and R² can be an N-linked alpha-amino acid ester andform a (SATE)-phosphonamidate diester prodrug.

The term “N-linked alpha-amino acid ester” refers to an amino acid thatis attached to the indicated moiety via a main-chain amino ormono-substituted amino group and wherein the main-chain carboxylic acidgroup has been converted to an ester group. Examples of alpha-aminoacids include, but are not limited to, alanine, asparagine, aspartate,cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine,arginine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, tryptophan and valine. When the amino acid isattached in an —N-linked amino acid, one of the hydrogens that is partof the main-chain amino or mono-substituted amino group is not presentand the amino acid is attached via the nitrogen. In embodiments, theester group has a formula selected from alkyl-O—C(═O)—,cycloalkyl-O—C(═O)—, aryl-O—C(═O)— and aryl(alkyl)-O—C(═O)—. N-linkedalpha-amino acid esters can be substituted or unsubstituted. When R¹and/or R² is an N-linked alpha-amino acid ester, the main-chain nitrogenof the main-chain amino or mono-substituted amino group is the nitrogenof Z¹ and/or Z², respectively. In embodiments, at least one of R¹ and R²can be

In embodiments, R¹ and R² both can be

In embodiments, R⁷ can be hydrogen. In embodiments, R⁷ can be anoptionally substituted C₁₋₈ alkyl. In embodiments, R⁷ can be a C₁₋₄alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyland t-butyl. In embodiments, R⁷ can be an optionally substitutedcycloalkyl, for example, an optionally substituted C₃₋₆ cycloalkyl or anoptionally substituted C₅₋₆ cycloalkyl. In embodiments, R⁷ can be anoptionally substituted aryl, such as an optionally substituted phenyl oran optionally substituted naphthyl. In embodiments, at least one of Z¹and Z² can be —O—. In embodiments, both Z¹ and Z² can be —O—. Inembodiments, R¹ and R² both can be a dioxolenone group and form adioxolenone prodrug.

In embodiments, R¹ and R² can be taken together to form an optionallysubstituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered ring system, and the “*” indicate the points of attachmentto Z¹ and Z², respectively. An example of and R² taken together to forman optionally substituted

wherein Z², R¹ and R², the phosphorus and the moiety form a six-memberedring system is the following:

When substituted, the ring of

can be substituted 1, 2, 3 or 3 or more times. When substituted withmultiple substituents, the substituents can be the same or different. Inembodiments, the

ring can be substituted with an optionally substituted aryl, anoptionally substituted heteroaryl or an optionally substitutedheterocyclyl. In embodiments, R¹ and R² can be taken together to form anoptionally substituted

such as

wherein R^(A) can be an optionally substituted phenyl, an optionallysubstituted mono-cyclic heteroaryl (such as pyridinyl) or an optionallysubstituted mono-cyclic heterocyclyl. In embodiments, R^(6A) and R^(7A)can form a cyclic 1-aryl-1,3-propanyl ester (HEPDIRECT™) prodrug moiety.

In embodiments, R¹ and R² can be taken together to form an optionallysubstituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form aten-membered ring system, and the “*” indicate the points of attachmentto Z¹ and Z², respectively. Example of an optionally substituted

includes

In embodiments, R¹ and R² can form a cyclosaligenyl (cycloSal) prodrug.An example of R¹ and R² taken together to form an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form aten-membered ring system is the following:

In embodiments, at least R¹ can be

wherein Z1 can be —NR^(Z)—, such as —NH—. In embodiments, R¹ and R² bothcan be

wherein Z¹ and Z² both can be —NR^(Z)—, such as —NH—. In embodiments, R⁹can be hydrogen. In embodiments, R⁹ can be an optionally substitutedC₁₋₆ alkyl. In embodiments, R¹⁰ can be hydrogen. In embodiments, R¹⁰ canbe an unsubstituted C₁₋₆ alkyl, —CH₂SH, —CH₂CH₂(C═O)NH₂, —CH₂CH₂SCH₃,CH₂— an optionally substituted phenyl, —CH₂OH, —CH(OH)CH₃,

—CH₂(C═O)OH, —CH₂CH₂(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

or —(CH₂)₄NH₂. In embodiments, R¹¹ can be hydrogen. In embodiments, R¹¹can be an optionally substituted C₁₋₈alkyl. In embodiments, R¹¹ can bean optionally substituted cycloalkyl, such as an optionally substitutedC₃₋₆ cycloalkyl. In embodiments, R¹¹ can be an optionally substitutedaryl. For example, R¹¹ can be a substituted or unsubstituted phenyl. Inembodiments, R¹¹ can be an optionally substituted aryl(C₁₋₆ alkyl) (suchas an optionally substituted benzyl).

When Z¹ and R¹, and/or Z² and R² form

can be N-linked alpha-amino acid ester. N-linked alpha-amino acid estersare described herein. In embodiments,

can be

In embodiments,

can be

In embodiments, R¹ can be

wherein Z¹ can be NH; and R² can be an optionally substituted aryl (forexample, an optionally substituted phenyl), and form an arylphosphonamidate prodrug. In embodiments, a compound of Formula (I) canbe a phosphorodiamidate prodrug, wherein R¹ and R² both can be

wherein Z¹ and Z² both can be —NR^(Z)—, such as —NH—.

When Z¹ and/or Z² are —NR^(Z)—, R^(Z) can be H (hydrogen) or anoptionally substituted C₁₋₄ alkyl. In embodiments, Z¹ and/or Z² can be—NH—. In embodiments, Z¹ and/or Z² can be —N— an optionally substitutedC₁₋₄ alkyl-. In embodiments, Z¹ and/or Z² can be —N— an unsubstitutedC₁₋₄ alkyl-. For example, Z¹ and/or Z² can be —N-methyl-, —N-ethyl-,—N-(n-propyl)-, —N-(iso-propyl)-, —N-(n-butyl)-, —N-(iso-butyl)- or—N-(t-butyl)-. In embodiments, the —N— an optionally substituted C₁₋₄alkyl can be —N(CH₂)—CH(OH)—CH₂OH.

In embodiments, at least one of R¹ and R² can be

In embodiments, R¹ and R² both can be

In embodiments, one of R¹ and R² can be

and the other of R¹ and R² can be an optionally substituted C₁₋₂₄ alkyl.In embodiments, at least one of Z¹ and Z² can be —O—. In embodiments,both Z¹ and Z² can be —O—. In embodiments, one of Z¹ and Z² can be —O—and the other of Z¹ and Z² can be —NR^(Z)—. Examples of prodrugs thatinclude

include the following:

In embodiments, a compound of Formula (I) can be a nitrofuranylmethylphosphonoamidate prodrug, wherein R¹ can be

R² can be —(CH₂)₃CH₂Cl, Z¹ can be O, and Z² can be NCH₃. In embodiments,a compound of Formula (I) can be a nitrofuranylmethyl N-dihydroxypropylphosphonoamidate prodrug, wherein R¹ can be

R² can be —(CH₂)₃CH₂Cl, Z¹ can be O, and Z² can be —N(CH₂)—CH(OH)—CH₂OH.

In embodiments, R¹ and R² can be the same. In embodiments, R¹ and R² canbe different.

As described herein, B¹ can be a naturally occurring guanine or amodified guanine base. For example, B¹ can be

wherein R³ can be an unsubstituted C₁₋₆ alkyl or an unsubstituted C₃₋₆cycloalkyl. In embodiments, R³ can be methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched or straightchained) or hexyl (branched or straight chained). In embodiments, R³ canbe cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Examples of compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, include, but are not limited to:

or a pharmaceutically acceptable salt of the foregoing.

Additional examples of Formula (I), or a pharmaceutically acceptablesalt thereof, include but are not limited to:

In embodiments, compounds have the Formula:

wherein R^(M) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group. The phenyl ring can be substituted by R^(M)1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carb amyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group. The phenyl ring can be substituted by R^(M)1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carb amyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group. The phenyl ring can be substituted by R^(M)1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In still another embodiment, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In another embodiment, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In one embodiment, compounds have the Formula:

wherein R^(M) is defined above. The phenyl ring can be substituted byR^(M) 1, 2 or 3 times.

In embodiments, R^(M) in a structure above is independently selectedfrom alkyl, alkoxy, halogen and cyano.

In embodiments, R¹ is an optionally substituted heteroaryl, for examplepyridine, pyrimidine, imidazole, pyrrole, furan or thiophene.

In embodiments, R¹ is an optionally substituted aryl including but notlimited to phenyl.

In embodiments, R¹ is optionally substituted aryl(C₁₋₄ alky).

In embodiments, R¹ is an optionally substituted heteroaryl, for examplepyridine, pyrimidine, imidazole, pyrrole, furan or thiophene and R² is—(CHR⁴)_(a)—O—(C₁₋₂₄ alkyl or alkenyl).

In embodiments, R¹ is optionally substituted aryl including, but notlimited, to phenyl and R² is —(CHR⁴)_(a)—O—(C₁₋₂₄ alkyl or alkenyl). Inembodiments, R¹ is optionally substituted aryl(C₁₋₄alky) and R² is—(CHR⁴)_(a)—O—(C₁₋₂₄ alkyl or alkenyl).

In embodiments, when R¹ is —(CH₂)₂—O—(CH₂)₁₇CH₃, then Z² cannot be O andR² cannot be phenyl (a substituted or unsubstituted phenyl). Inembodiments, when R¹ is —(CH₂)₂—O—(CH₂)₁₇CH₃, then Z² cannot be O and R²cannot be benzyl (a substituted or unsubstituted benzyl). Inembodiments, when R¹ is —(CH₂)₂—O—(CH₂)₁₇CH₃, then Z² cannot be O and R²cannot be hydrogen. In embodiments, when R is —(CH₂)₃—O—(CH₂)₁₅CH₃, thenZ² cannot be O and R² cannot be phenyl (a substituted or unsubstitutedphenyl). In embodiments, when R¹ is —(CH₂)₃—O—(CH₂)₁₅CH₃, then Z² cannotbe O and R² cannot be benzyl (a substituted or unsubstituted benzyl). Inembodiments, when R¹ is —(CH₂)₃—O—(CH₂)₁₅CH₃, then Z² cannot be O and R²cannot be hydrogen. In embodiments, R¹ cannot be —(CH₂)_(a)—O—C₁₋₂₄alkyl. In embodiments, the human papillomavirus cannot be HPV-16 and/orHPV-18. In embodiments, the human papillomavirus cannot be HPV-11.

Without being bound by any particular theory, it is possible thatrapidly dividing epithelial cells cannot effectively repair PMEGterminated viral primers. In embodiments the compounds described hereinrelease PMEG very slowly thereby moderating intracellular levels of PMEGdiphosphate, the active metabolite favoring antiviral activity andinhibition of HPV DNA synthesis, while higher intracellular levels ofPMEG diphosphate (resulting from prodrugs that release PMEG diphosphatemore quickly in the cell) lead to inhibition of cell division in anumber of human cancers. It has been discovered herein, inter alia, thatthe anti-proliferative activity of the active metabolite PMEGdiphosphate may be separated from the antiviral action of the activemetabolite PMEG diphosphate by careful selection of the prodrug moietyto moderate the release rate of the active metabolite in the cell.

Pharmaceutical Compositions

There are provided pharmaceutical compositions that can include aneffective amount of one or more compounds described herein (e.g., acompound of Formula (I) or embodiment thereof, or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable carrier,diluent, excipient or combination thereof. In embodiments, thepharmaceutical composition can include a single diastereomer of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,(for example, a single diastereomer is present in the pharmaceuticalcomposition at a concentration of greater than 99% compared to the totalconcentration of the other diastereomers). In embodiments, thepharmaceutical composition can include a mixture of diastereomers of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.For example, the pharmaceutical composition can include a concentrationof one diastereomer of >50%, ≧60%, ≧70%, ≧80%, ≧90%, ≧95%, or ≧98%, ascompared to the total concentration of the other diastereomers. Inembodiments, the pharmaceutical composition includes a 1:1 mixture oftwo diastereomers of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

The term “pharmaceutical composition” refers to a mixture of one or morecompounds disclosed herein with other chemical components, such asdiluents or carriers. The pharmaceutical composition facilitatesadministration of the compound to an organism. Pharmaceuticalcompositions can also be obtained by reacting compounds with inorganicor organic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid and salicylic acid. Pharmaceuticalcompositions will generally be tailored to the specific intended routeof administration. A pharmaceutical composition is suitable for humanand/or veterinary applications.

The term “physiologically acceptable” defines a carrier, diluent orexcipient that does not abrogate the biological activity and propertiesof the compound.

As used herein, a “carrier” refers to a compound that facilitates theincorporation of a compound into cells or tissues. For example, withoutlimitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrierthat facilitates the uptake of many organic compounds into cells ortissues of a subject.

As used herein, a “diluent” refers to an ingredient in a pharmaceuticalcomposition that lacks pharmacological activity but may bepharmaceutically necessary or desirable. For example, a diluent may beused to increase the bulk of a potent drug whose mass is too small formanufacture and/or administration. It may also be a liquid for thedissolution of a drug to be administered by injection, ingestion orinhalation. A common form of diluent in the art is a buffered aqueoussolution such as, without limitation, phosphate buffered saline thatmimics the composition of human blood.

As used herein, an “excipient” refers to an inert substance that isadded to a pharmaceutical composition to provide, without limitation,bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. A “diluent” is a typeof excipient.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orcarriers, diluents, excipients or combinations thereof. Properformulation is dependent upon the route of administration chosen.Techniques for formulation and administration of the compounds describedherein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. Additionally, theactive ingredients are contained in an amount effective to achieve itsintended purpose. Many of the compounds used in the pharmaceuticalcombinations disclosed herein may be provided as salts withpharmaceutically compatible counterions.

Multiple techniques of administering a compound exist in the artincluding, but not limited to, oral, rectal, topical, aerosol, injectionand parenteral delivery, including intramuscular, subcutaneous,intravenous, intramedullary injections, intrathecal, directintraventricular, intraperitoneal, intranasal, intravaginal andintraocular injections.

One may also administer the compound in a local rather than systemicmanner, for example, via application of the compound directly to theinfected area. The compound can be administered as a gel, a cream and/ora suppository. In addition, the compound can be administered in a depotor sustained release formulation (for example, as nanoparticles and/oran intravaginal ring). Furthermore, one may administer the compound in atargeted drug delivery system, for example, in a liposome coated with atissue-specific antibody. The liposomes will be targeted to and taken upselectively by the organ.

The compositions may, if desired, be presented in a pack, applicator ordispenser device which may contain one or more unit dosage formscontaining the active ingredient. The pack may for example comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration. The packor dispenser may also be accompanied with a notice associated with thecontainer in form prescribed by a governmental agency regulating themanufacture, use, or sale of pharmaceuticals, which notice is reflectiveof approval by the agency of the form of the drug for human orveterinary administration. Such notice, for example, may be the labelingapproved by the U.S. Food and Drug Administration for prescriptiondrugs, or the approved product insert. Compositions that can include acompound described herein formulated in a compatible pharmaceuticalcarrier may also be prepared, placed in an appropriate container, andlabeled for treatment of an indicated condition.

Synthesis

Compounds of Formula (I) and those described herein may be prepared invarious ways. General synthetic routes to the compound of Formula (I)and some examples of starting materials used to synthesize compounds ofFormula (I) are shown in Schemes 1 and 2, and described herein. Theroutes shown and described herein are illustrative only and are notintended, nor are they to be construed, to limit the scope of the claimsin any manner whatsoever. Those skilled in the art will be able torecognize modifications of the disclosed syntheses and to devisealternate routes based on the disclosures herein; all such modificationsand alternate routes are within the scope of the claims.

A shown in Scheme 1, the acyclic nucleoside phosphonate can be coupledwith R¹-LG and/or R²-LG, wherein LG is a suitable leaving groups (forexample, Cl). Alternatively, the OH groups attached to the phosphoruscan be transformed and then replaced with R¹ and/or R². For example, thehydrogens of the OH groups can be transformed to alkali metal ions, suchas Na+ (shown as R′ in Scheme 1). Methods for coupling an acyclicnucleoside phosphonate are known to those skilled in the art. Forexamples, see methods described and referenced in Pradere, U. et al.,Chem. Rev., 2014, 114:9154-9218.

EXAMPLES Example 1 9-[(2-phosphonomethoxy)ethyl]-2-amino-6-chloropurine,tributylamine salt (7)

Compound 6 was prepared as shown in Scheme A and converted to thephosphonic acid (6-a) by treatment with bromotrimethylsilane, followedby hydrolysis. The detailed methods are described in Holy, A. et al. J.Med. Chem. (1999) 42(12):2064-2086. To prepare 7, a 1 L flask wasequipped with a magnetic stirrer, a nitrogen inlet, and an additionfunnel. Compound 6-a (18.8 g, 61 mmol) and N,N-DMF (200 mL) were added,and the resulting slurry was stirred. Tributylamine (14.9 mL, 62 mmol)was added dropwise over 15-20 mins. The resulting solution was stirredat ambient temperature for 10 mins. Toluene (470 mL) was added, andstirring was continued for 30-40 mins. Seed crystals (50 mg) of compound7 were added. The mixture was stirred for 5 h, after which theprecipitated solids were filtered. The solids were washed with toluene(150 mL) and dried under vacuum for several hours to give 7 (25.6 g, 85%yield) as an off-white powder. The solid was analyzed by ¹H NMR and ³¹PNMR spectroscopy. ¹H NMR (DMSO-d₆) δ 8.20 (s, 1H), 6.91 (s, 2H), 4.20(t, 2H), 3.81 (t, 2H), 3.45 (d, 2H), 2.73 (m, 2H), 1.51 (m, 2H), 1.26(septet, 2H), 0.87 (t, 3H).

The spectra were found to be consistent with 7.

Example 2 9-[(2-phosphonomethoxy)ethyl]guanine (PMEG, 9)

Compound 9 was prepared by acidic hydrolysis of 6 as shown in Scheme B.Compound 6 (4.95 g, 12.6 mmol) was dissolved in 80% aq. CH₃COOH. Themixture was stirred and heated at reflux for 3 h. The mixture was thencooled. The solvent was evaporated under vacuum to give crude 8 as anoff-white powder, which was dried in a vacuum oven at 45° C. Compound 8was dissolved in CH₃CN (30 mL), treated with bromotrimethylsilane (11.6g, 76 mmol) and stirred overnight. The mixture was evaporated undervacuum. Water/crushed ice (50 mL) was added to the residue. The slurrywas stirred for 1 h, and the precipitate was collected by filtration toprovide 9 (PMEG, 3.1 g, 85% yield). Additional details for preparingPMEG are described in Holy, A. et al. J. Med. Chem. (1999)42(12):2064-2086.

Example 3 Octadecyloxyethyl PMEG (ODE-PMEG, 11)

Method A: Compound 11 was prepared by esterification of 7 according toScheme C. A 1 L flask was equipped with a magnetic stirrer, thencompound 7 (21.7 g, 44 mmol), 2-octadecyloxyethanol (ODE-OH, 14.2 g, 45mmol) and anhydrous N,N-DMF (300 mL) were added. The mixture was stirredand (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 35 g, 67.5 mmol) was subdivided in five equal portions (7 geach) and each portion was then added at 30 mins intervals. After theaddition of PYBOP®, diisopropylethylamine (DIEA, 5.8 g, 45 mmol) and1-hydroxybenzotriazole (HOBt, 3.0 g, 22.5 mmol) were added. Theresulting mixture was stirred at 22-25° C., and the progress of thereaction was monitored by TLC (70:30:3:3 CHCl₃:MeOH:conc. NH₄OH:H₂O) onsilica gel plates (Analtech, UNIPLATES™ Silica gel G, 250 microns).After the reaction was judged complete (16-20 h), the reaction mixturewas slowly poured into a stirred acidic mixture comprised of conc. HCl(10 mL), water (750 mL) and crushed ice (750 mL). Stirring was continuedfor 10 mins. The precipitated solid was collected by filtration, washedwith cold water (2×100 mL) and dried under vacuum to give crude 10 (32.7g). The crude product was purified by silica gel column chromatographywith elution of the product by CH₂Cl₂:MeOH 90:10 to yield 10 (9.5 g,30.7% yield).

A 1 L reaction flask was equipped with a magnetic stirrer and acondenser. Compound 10 (9.5 g, 13.5 mmol), acetic acid (240 mL) andwater (60 mL) were added. The resulting mixture was stirred and heatedto reflux. The progress of the reaction was monitored by TLC (70:30:3:3CHCl₃:MeOH:conc. NH₄OH:H2O) on silica gel plates (Analtech, UNIPLATES™Silica gel G, 250 microns) using a UV lamp and charring. After thereaction was complete (3.5 h), the reaction mixture was cooled to 5° C.,stirred for 2 h and filtered. The product was dried under vacuum to give11 (7.5 g). The crude product was recrystallized in 80:20isopropanol:water. After treatment with decolorizing carbon, thefiltrate was allowed to cool to room temperature (RT) and then in anice-bath. The precipitated solids were filtered and dried under vacuumto give 11 (6.2 g, 78%) as off-white powder.

Method B: Octadecyloxyethyl 9-[2-(phosphonomethoxy)ethyl]guanine(ODE-PMEG) was prepared according to the method described in Valiaeva,N. et al.; Antiviral Research (2006) 72:10-19.

Example 4 Benzyl PMEG (Bn-PMEG, 13)

Compound 13 was prepared by esterification of 7 with benzyl alcoholaccording to Scheme D. A 100 mL flask was equipped with a magneticstirrer, then compound 7 (2.0 g, 4 mmol), benzyl alcohol (860 mg, 8mmol) and anhydrous N,N-DMF (30 mL) were added. The mixture was stirred.(Benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 3.2 g, 6 mmol) was subdivided in five equal portions (640 mgeach) and each portion was then added at 30 mins intervals. After theaddition of PYBOP®, diisopropylethylamine (DIEA, 516 mg, 4 mmol) and1-hydroxybenzotriazole (HOBt, 270 mg, 2 mmol) were added. The reactionmixture was stirred at 22-25° C., and the progress of the reaction wasmonitored by TLC (70:30:3:3 CHCl₃:MeOH:conc. NH₄OH: H₂O) on silica gelplates (Analtech, UNIPLATES™ Silica gel G, 250 microns). After thereaction was judged complete (16-20 h), the reaction mixture wasconcentrated in vacuo. The crude product was purified by silica gelcolumn chromatography with elution of the product by CH₂Cl₂:MeOH 55:45to yield 12 (840 mg).

A 100 mL reaction flask was equipped with a magnetic stirrer and acondenser. Compound 12 (840 mg), acetic acid (24 mL) and water (6 mL)were added. The resulting mixture was stirred and heated to reflux. Theprogress of the reaction was monitored by TLC (70:30:3:3CHCl₃:MeOH:conc. NH₄OH:H₂O) on silica gel plates (Analtech, UNIPLATES™Silica gel G, 250 microns) using a UV lamp and charring. After thereaction was complete (3 h), the reaction mixture was evaporated undervacuum. The product was dried under vacuum to afford 13 (7.5 g). Thecrude product was purified by silica gel column chromatography withelution of the product by CH₂Cl₂:MeOH 50:50 to yield purified 13 (620mg) as an off-white powder. ¹H NMR (400 MHz, CDCl₃+methanol) δ 7.87 (s,1H) 7.20-7.36 (m, 5H) 4.92 (d, J=7.33 Hz, 2H) 4.17 (br. s., 2H) 3.78(br. s., 2H) 3.66 (d, J=8.07 Hz, 2H).

Example 5 1-O—Octadecyl-2-O-benzyl-sn-glyceryl PMEG (ODBG-PMEG, 14)

ODBG-PMEG was prepared by esterification of 7 with1-O-octadecyl-2-O-benzyl-sn-glycerol (ODBG-OH). A 500 mL flask wasequipped with a magnetic stirrer, then compound 7 (9.0 g, 18.25 mmol),ODBG-OH (20.7 mmol) and anhydrous N,N-DMF (200 mL) were added. Themixture was stirred and (benzotriazol-1-yloxy)-tripyrrolidinophosphoniumhexafluorophosphate (PYBOP®, 15.6 g, 30 mmol) was subdivided in 3 equalportions (5.2 g each) and each portion was then added at 30 minsintervals. After the addition of PYBOP®, diisopropylethylamine (DIEA,2.6 g, 20 mmol) and 1-hydroxybenzotriazole (HOBt, 1.2 g, 9 mmol) wereadded. The reaction mixture was stirred at 22-25° C., and the progressof the reaction was monitored by TLC (70:30:3:3 CHCl₃:MeOH:conc. NH₄OH:H₂O) on silica gel plates (Analtech, UNIPLATES™ Silica gel G, 250microns). After the reaction was judged complete (16-20 h), the reactionmixture was concentrated in vacuo. The crude product was purified bysilica gel column chromatography with elution of the product byCH₂Cl₂:EtOH 80:20 to yield the esterified intermediate (7.5 g, 50%yield).

A 500 mL reaction flask was equipped with a magnetic stirrer and acondenser. The esterified intermediate from the previous step (7.5 g),acetic acid (80 mL) and water (20 mL) were added. The resulting mixturewas stirred and heated to reflux. The progress of the reaction wasmonitored by TLC (70:30:3:3 CHCl₃:MeOH:conc. NH₄OH:H₂O) on silica gelplates (Analtech, UNIPLATES™ Silica gel G, 250 microns) using a UV lampand charring. After the reaction was complete (3 h), the reactionmixture was evaporated under vacuum. The crude product was purified bysilica gel column chromatography with elution of the product byCH₂Cl₂:MeOH 80:20 to yield 14 (5.2 g, 81% yield) as an off-white powder.

Example 6 Acyloxyalkyl ester of 9-[2-(phosphonomethoxy)ethyl]-guanine

Acyloxyalkyl esters of PMEG are prepared using methods similar to thosedescribed by Srivasta, et al. Bioorg. Chem. (1984) 12:118-129 andStarrett et al. J. Med. Chem. (1994) 37 1857-1864. A typical approach tosynthesis is shown in Scheme E.

Example 7 (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of9-[2-(phosphonomethoxy)-ethyl]guanine

9-[2-(phosphonomethoxy)ethyl]-guanine (PMEG) is neutralized with a 1Msolution of methanolic tetrabutylammonium bromide in MeOH. The solutionis evaporated and co-distilled with EtOH and toluene. The residue isdissolved in anhydrous DMF and treated with(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide at RT for 4 daysaccording to the procedure for preparing the corresponding adefovirprodrugs (see Tichý et al., Bioorg. & Med. Chem. (2011)19(11):3527-3539.

Example 8 S-acylthioethyl (SATE) esters of PMEG

The general procedure for the synthesis of (S-acylthioethyl) (SATE)esters of PMEG are shown in Scheme G. Procedures are analogous to thosedescribed for preparing the adefovir SATE esters in Benzaria, S. et al.,J. Med. Chem. (1996) 39(25):4958-4965.

Example 9 bis[S-2-hydroxyethylsulfidyl)-2-thioethyl]esters of PMEG

Bis[S-2-hydroxyethylsulfidyl)-2-thioethyl] PMEG esters (Scheme H) areprepared following similar procedures provided in Puech, F. et al.Antiviral Research (1993) 22:155-174.

Example 10 Aryl Phosphonoamidate PMEG Prodrugs

Aryl phosphonoamidate PMEG prodrugs are prepared following similarprocedures provided in U.S. Pat. No. 8,088,754. Examples are shownbelow.

Synthesis of9-[2-(phenyloxy-(ethoxy-L-alaninyl))-phosphonomethoxy)ethyl]guanine:

To a solution of diisopropyl PMEG (1.0 g, 3 mmol) in dry acetonitrile(30 mL), bromotrimethylsilane (2.3 g, 15 mmol) was added and thereaction was stirred at room temperature overnight. The solvents werethen removed under vacuum. The residue was dissolved in anhydrous Et3N(6 mL) and pyridine (25 mL), L-alanine ethyl ester HCl (0.69 g, 4.5mmol) and phenol (0.42 g, 4.5 mmol) were added. A solution ofAldrithiol-2 (4.0 g, 18 mmol eq) and Ph₃P (4.7 g, 18 mmol) in anhydrouspyridine (30 ml) was added to the reaction. The resulting mixture washeated to 50° C. and stirred for 3 hours. After cooling, the solventswere removed under reduced pressure and the residue was adsorbed onsilica gel. The product was isolated as a mixture of diastereomers byflash chromatography on silica gel eluted with 0 to 5% MeOH indichloromethane (410 mg, 29%). ¹H NMR (DMSO-d6) δ 10.65 (s, 2H), 7.69(s, 1H), 7.68 (s, 1H), 7.35-7.30 (m, 4H), 7.17-7.11 (m, 6H), 6.52 (s,4H), 5.71 (t, 4H), 5.64 (t, 4H), 4.15-4.11 (m, 2H), 4.03-3.99 (m, 2H),3.91-3.81 (m, 4H), 3.36 (s, 2H), 3.07 (q, 2H), 1.20 (d, 3H), 1.15 (d,3H), 1.13 (t, 6H). MS (ESI) 465.20 [M+H]+, 487.19 [M+Na]+, 509.17M−H+2Na]+.

Example 11 Bis(phosphonoamidate) PMEG Prodrugs

Bis(phosphonoamidate) PMEG prodrugs are prepared following similarprocedures provided in U.S. Pat. No. 8,088,754. Examples are shownbelow.

The compound9-[2-(bis-(ethyloxy-L-alaninyl)-phosphonomethoxy)ethyl]guanine,illustrated above, was prepared as described in Lansa, P. et al.European Journal of Medicinal Chemistry, 2011, 46:3748-3754.

Example 12 Cyclic 1-aryl-1,3-propanyl PMEG esters

Cyclic 1-aryl-1,3-propanyl PMEG esters are prepared following similarprocedures provided in Reddy, et al., J. Med. Chem. (2008) 51:666-676. Ageneral procedure for preparing cyclic 1-aryl-1,3-propanyl PMEG estersis shown in Scheme I.

Example 13 Cyclosal PMEG Esters

Cyclosal PMEG esters are prepared following similar procedures providedin Meier, C. et al., J. Med. Chem. (2005) 48:8079-8086. A generalprocedure for preparing cyclosal PMEG esters is shown in Scheme J.

Example 14 Nitrofuranylmethyl PMEG Prodrugs

Nitrofuranylmethyl phosphonoamidate derivatives of PMEG are synthesizedby sequential esterification of compound 7 with 5-nitrofurfuryl alcoholand N-methyl-N-4-chlorobutylamine as depicted in Scheme K. Thenitrofuranylmethyl group has been shown (Tobias, S. C. et al., Mol.Pharmaceutics (2004) 1:112-116) to be readily taken up by cells, thencleaved intracellularly by a reductase enzyme which, in turn, leads tothe formation of an intermediate chlorobutyl phosphonoamidate.Cyclization of the intermediate by nucleophilic attack of the nitrogenatom forms an N-phosphonotrialkyl ammonium species that can afford theunmasked phosphonate PMEG after hydrolysis.

Example 15 Synthesis of ODE-(4-Me-Bn)-PMEG

ODE-PMEG (150 mg, 0.26 mmol), 4-methylbenzyl alcohol (70 mg, 0.52 mmol)and (1H-bentriazol-1-yloxy)-tripyrrolidinophosphonium hexafluoride(PyBOP, 200 mg, 0.4 mmol) were weighed into a dried 100 mL round bottomflask. Anhydrous N,N-dimethylformamide (5 mL) and diisopropylethylamine(0.1 mL, 0.52 mmol) were then added and the reaction was stirred at roomtemperature for 4 hours. The mixture was then concentrated under vacuumto an oil. The residue was adsorbed on silica gel and the product wasisolated by column chromatography on silica gel (eluant: 0 to 10% MeOHin dichloromethane) to yield ODE-(4-Me-Bn)-PMEG as an off-white waxysolid. (60 mg, 33% yield). ¹H NMR (400 MHz, CDCl₃+methanol-d4) δ 7.64(s, 1H) 7.22-7.28 (m, 2H) 7.15-7.20 (m, 2H) 5.04 (dd, J=8.80, 2.20 Hz,2H) 4.19 (t, J=4.95 Hz, 2H) 4.12 (m, 2H) 3.82-3.87 (m, 2H) 3.55-3.59 (m,2H) 3.43 (t, J=6.60 Hz, 2H) 3.35 (dt, J=3.30, 1.65 Hz, 2H) 2.35 (s, 3H)1.49-1.60 (m, 2H) 1.16-1.37 (m, 30H) 0.86 (t, J=7 Hz, 3H). MS (ESI):690.67 (M+H)+, 712.53 (M+Na)+, 734.51 (M+2Na−H)+.

Example 16 Synthesis of ODE-(3-F-4-OMe-Bn)-PMEG

ODE-(3-F-4-OMe-Bn)-PMEG was prepared by the method of Example 4, using3-fluoro-4-methoxybenzyl alcohol. The product was obtained as a waxysolid (100 mg, 52%). ¹H NMR (400 MHz, CDCl₃+methanol-d4) δ 7.65 (s, 1H)7.06-7.17 (m, 2H) 6.96-7.05 (m, 1H) 5.00 (dd, J=8.80, 1.83 Hz, 2H) 4.21(t, J=5.13 Hz, 2H) 4.14 (m, 2H) 3.81-3.93 (m, 2H) 3.59 (dd, J=4.95, 3.85Hz, 2H) 3.45 (t, J=6.78 Hz, 2H) 3.35 (s, 3H) 1.49-1.60 (m, 2H) 1.07-1.45(m, 30H) 0.86 (t, J=7 Hz, 3H). MS (ESI): 724.56 (M+H)+, 746.49 (M+Na)+.

Example 17 Synthesis of ODE-(3-Cl-4-OMe-Bn)-PMEG

ODE-(3-Cl-4-OMe-Bn)-PMEG was prepared by the method of Example 4, using3-chloro-4-methoxybenzyl alcohol. The product was obtained as a waxysolid (90 mg, 46%). ¹H NMR (400 MHz, CDCl₃+methanol-d₄) δ ppm 7.66 (s.,1H) 7.64-7.68 (m, 1H) 7.38-7.42 (m, 1H) 7.40 (d, J=2.20 Hz, 1H)4.95-5.05 (m, 2H) 4.21 (t, J=5.13 Hz, 2H) 4.11-4.17 (m, 2H) 3.87-3.91(m, 2H) 3.84-3.89 (m, 2H) 3.58 (dd, J=4.95, 3.85 Hz, 2H) 3.44 (t, J=6.60Hz, 2H) 3.35 (s, 3H) 1.51-1.59 (m, 2H) 1.06-1.45 (m, 30H) 0.89 (t, J=7Hz, 3H).). MS (ESI): 740.52 (M+H)+, 762.47 (M+Na)+.

Example 18 Synthesis of ODE-(3-F-Bn)-PMEG

ODE-(3-F-Bn)-PMEG was prepared by the method of Example 4, using3-fluorobenzyl alcohol. The product was obtained as an off-white solid(80 mg, 44%). ¹H NMR (400 MHz, CDCl₃+methanol-d₄) δ 7.64 (s, 1H)7.42-7.50 (m, 1H) 7.33-7.40 (m, 1H) 6.97-7.19 (m, 2H) 5.03-5.16 (m, 2H)4.11-4.25 (m, 4H) 3.84-3.95 (m, 2H) 3.55-3.65 (m, 2H) 3.41-3.49 (m, 4H)3.35 (s, 3H) 1.49-1.61 (m, 2H) 1.07-1.39 (m, 30H) 0.88 (t, J=7 Hz, 3H).MS (ESI): 694.45 (M+H)+, 716.44 (M+Na)+, 738.44 (M+2Na−H)+.

Example 19 Synthesis of ODE-(3-Cl-Bn)-PMEG

ODE-(3-Cl-Bn)-PMEG was prepared by the method of Example 4, using3-chlorobenzyl alcohol. The product was obtained as an off-white solid(80 mg, 42%). ¹H NMR (400 MHz, CDCl₃+methanol-d₄) δ 7.63 (s, 1H) 7.45(t, J=6.42 Hz, 1H) 7.23-7.41 (m, 3H) 5.06 (d, J=8.80 Hz, 2H) 4.17-4.21(m, 4H) 3.80-3.94 (m, 4H) 3.59 (d, J=4.77 Hz, 2H) 3.44 (t, J=6.78 Hz,2H) 3.36 (s, 4H) 1.50-1.56 (m, 2H) 1.11-1.24 (m, 30H) 0.88 (t, J=6.78Hz, 3H). MS (ESI) [M+H]+ 710.46, [M+Na]+732.43.

Example 20 Synthesis of ODE-(3-picolyl)-PMEG

ODE-(3-picolyl)-PMEG was prepared by the method of Example 4, using3-pyridinemethanol. The product was obtained as an off-white solid (110mg, 40%). ¹H NMR (400 MHz, CDCl₃+methanol-d₄) δ 7.60 (s, 1H) 7.40-7.42(m, 1H) 7.23-7.31 (m, 3H) 5.16 (d, J=8.80 Hz, 2H) 4.15-4.20 (m, 4H)3.86-3.95 (m, 4H) 3.56-3.60 (m, 2H) 3.41-3.49 (m, 2H) 3.36 (s, 3H)1.50-1.56 (m, 2H) 1.11-1.24 (m, 30H) 0.88 (t, J=6.78 Hz, 3H). MS (EI):677.46 (M+H)+, 699.47 (M+Na)+, 721.41 (M+2Na-H)+.

Example 21 Low Risk and High Risk HPV Assays

An origin-containing low risk or high risk HPV plasmid wasco-transfected with homologous E1 and E2 protein expression vectors intoHEK 293 cells. At 4 h post-transfection, cells were treated with testcompound dilutions and then incubated for 48 h. HPV origin plasmidreplication was detected after digestion with DpnI and exonuclease IIIto remove unreplicated transfected plasmids. Remaining replicated DNAwas quantified by quantitative real time PCR (qPCR). In a parallelexperiment in uninfected cells cytotoxicity was determined by trypanblue exclusion or CELLTITER-GLO® to find the concentration that reducedviable cell number by 50% (CC50). CC50 values were determined by trypanblue exclusion or CELLTITER-GLO® and the selectivity index calculated(Selectivity index=CC50/EC50). The low risk HPV tested was HPV-11, andthe high-risk HPV tested was HPV-16 and HPV-18.

The results are provided in Table A and Table B following. As shown inTable A, compounds of Formula (I) are active against both low-risk andhigh-risk HPV.

TABLE A Compound Low Risk High Risk PMEG C C ODE-PMEG A A ODBG-PMEG B B‘A’ indicates an EC₅₀ <0.3 μM, ‘B’ indicates an EC₅₀ of ≧0.3 μM and <3.0μM and ‘C’ indicates an EC₅₀ ≧3.0 μM and <30 μM. For all the testedcompounds, the selectivity indexes were >10.

The results are provided in Table B. As shown in Table B, compounds ofFormula (I) are active against both low-risk and high-risk HPV.

TABLE B Antiviral Activity against HPV-11 in HEK-293 Cells Compound EC₅₀(μM) EC₉₀ (μM) CC₅₀ (μM) SI₅₀ ODE-(4-Me-Bn)-PMEG 0.93 ± 0.91  7.0 ± 3.45 23.80 ± 19.52 26 ODE-(3-F-4-OMe-Bn)- 0.18 ± 0.04 0.99 ± 0.13 14.25 ±9.48 79 PMEG ODE-(3-Cl-4-OMe Bn)- 0.68 ± 0.62 1.34 ± 0.78  8.31 ± 1.8312 PMEG ODE-(3-F-Bn)-PMEG 0.26 ± 0   1.59 ± 0.57  1.74 ± 0.03 7 PMEGbisamidate 5.04 ± 7.01 >100 ± 0   >100 ± 0  >20 Example 11 PMEG phenoxyamidate 7.56 ± 0.63 >100 ± 0   >100 ± 0  >13 Example 10ODE-(3-Cl-Bn)-PMEG 0.22 ± 0.19 >0.4 ± 0    1.11 ± 0.27 5 Cidofovir 41.71± 12   >300 ± 0   >300 ± 0  >7

Example 22 Cytotoxicity Assay

Cytotoxicity Assays in HEK-293 cells. Cytotoxicity assays are performedin concurrently with every antiviral assay using the same cell line andmedia to ensure the same compound exposure. For the antiviral studiesagainst HPV11 in HEK-293 cells, transfected cells are seeded induplicate plates. Following a 2 h exposure, compound dilutions areprepared in both the antiviral plate and the duplicate cytotoxicityplate. At 48 h following compound addition, CELLTITER-GLO® (Promega) isadded to each well and luminescence is determined on a luminometer.Concentrations of compounds sufficient to reduce cell viability by 50%are calculated from the experimental data (CC50 values).

Cytotoxicity Assays in Primary Human Foreskin Fibroblast Cells.Cytotoxicity was also evaluated in human foreskin fibroblast (HFF) cellsas they are a highly sensitive indicator of toxicity in a standard assaywith 7 d of compound exposure. A total of 4000 cells/well are seeded in384-well plates in cell culture media containing 2% fetal bovine serumand antibiotics. Following a 24 h incubation, 5-fold compound dilutionsare performed in duplicate wells directly in the plates containingmonolayers of HFF cells. At 7 d following compound addition,CellTiter-Glo reagent is added to each well and resulting luminescenceis measured on a luminometer to assess the number of viable cells ineach well. Data are then used to calculate CC50 values. The data isdisclosed in Table 2 below.

TABLE 2 Cytotoxicity Results (CellTiter-Glo) (CC₅₀, μM) HEK 293 HFFCompound (2 d incubation) (7 d incubation) ODE-(4-Me-Bn)-PMEG 32.01 ±8.14 6.02 ± 3.79 ODE-(3-F-4-OMe-Bn)-PMEG 13.08 ± 5.17 1.72 ± 0.66ODE-(3-Cl-4-OMe-Bn)-  8.87 ± 1.20 2.27 ± 0.51 PMEG ODE-(3-F-Bn)-PMEG 2.16 ± 0.36 6.88 ± 4.92 PMEG bisamidate >100 ± 0  >100 ± 0   Example 11PMEG phenoxy amidate >100 ± 0  70.93 ± 4.07  Example 10ODE-(3-Cl-Bn)-PMEG  1.0 ± 0.16 4.65 ± 1.73 Cidofovir >300 ± 0  >300 ±0  

Example 23 Synthesis of9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylaminesalt, 1, alternate name:((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphonic acid,tributylamine salt

The scheme above provides a chemical synthetic scheme to afford9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylaminesalt.

Example 24 Synthesis of octadecyloxyethyl9-[(2-phosphonomethoxy)ethyl]6-O-Me-guanine

The scheme above provides a chemical synthetic scheme to afford9-[(2-phosphonomethoxy)ethyl]6-O-Me-guanine.

Example 25 Synthesis of benzyl9-[(2-phosphonomethoxy)ethyl]6-O-Me-guanine

The scheme above provides a chemical synthetic scheme to afford benzyl9-[(2-phosphonomethoxy)ethyl]6-O-Me-guanine.

Example 26 Synthesis of 1-O-octadecyl-2-O-benzyl-sn-glyceryl9-[(2-phosphono-methoxy)ethyl]6-O-Me-guanine

The scheme above provides a chemical synthetic scheme to afford1-O-octadecyl-2-O-benzyl-sn-glyceryl9-[(2-phosphono-methoxy)ethyl]6-O-Me-guanine.

Example 27 Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl hydrogen((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphonate

The scheme above provides a chemical synthetic scheme to afford(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl hydrogen((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl) phosphonate.

Example 28 Synthesis ofS,S′-(((((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl))diethanethioate

The scheme above provides a chemical synthetic scheme to affordS,S′-(((((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl))diethanethioate.

Example 29 Synthesis of bis(2-((2-hydroxyethyl)sulfinothioyl)ethyl)((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphonate

The scheme above provides a chemical synthetic scheme to affordbis(2-((2-hydroxyethyl)sulfinothioyl)ethyl)((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl) phosphonate.

Example 30 Synthesis of2-amino-9-(2-((4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl)methoxy)ethyl)-1,9-dihydro-6H-purin-6-one

The scheme above provides a chemical synthetic scheme to afford2-amino-9-(2-((4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl)methoxy)ethyl)-1,9-dihydro-6H-purin-6-one.

Example 31 Synthesis of2-((2-(2-amino-6-hydroxy-9H-purin-9-yl)ethoxy)methyl)-8-(tert-butyl)-4H-benzo[d][1,3,2]dioxaphosphinine2-oxide

The scheme above provides a chemical synthetic scheme to afford2-((2-(2-amino-6-hydroxy-9H-purin-9-yl)ethoxy)methyl)-8-(tert-butyl)-4H-benzo[d][1,3,2]dioxaphosphinine2-oxide.

Example 32 Synthesis of (5-nitrofuran-2-yl)methylP-((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)-N-(4-chlorobutyl)-N-methylphosphonamidate

The scheme above provides a chemical synthetic scheme to afford(5-nitrofuran-2-yl)methylP-((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)-N-(4-chlorobutyl)-N-methylphosphonamidate.

Example 33 Synthesis of dibenzyl PMEG

Dibenzyl PMEG can be prepared from benzyl PMEG, Example 4, asillustrated below.

Example 34 Synthesis of dibenzyl9-[(2-phosphonomethoxyl)ethyl]6-OMe-guanine

Dibenzyl 9-[(2-phosphonomethoxyl)ethyl]6-OMe-guanine can be preparedfrom 9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine,tributylamine salt (Example 23).

Example 35 Synthesis of octadecyloxyethyl benzyl9-[(2-phosphonomethoxyl)ethyl]6-OMe-guanine

The compound octadecyloxyethyl benzyl9-[(2-phosphonomethoxyl)ethyl]6-OMe-guanine can be prepared from9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylaminesalt (Example 23) as illustrated below.

Example 36 Synthesis of hexadecyloxypropyl benzyl9-[2-phosphonomethoxyl)ethyl]6-OMe-guanine

The compound hexadecyloxypropyl benzyl9-[(2-phosphonomethoxyl)ethyl]6-OMe-guanine can be prepared from9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylaminesalt (Example 23) as illustrated below.

Example 37 Synthesis of a Nitrofuranylmethyl PMEG Prodrug

Benzyl PMEG is treated with 5-nitrofurfuryl alcohol, ByBOP,diisopropylethylamine, and N,N-dimethylformamide for 18 hours at roomtemperature as illustrated below.

Example 38 Synthesis of a Nitrofuranylmethyl Benzyl Prodrug

The compound benzyl 9-[(2-phosphonomethoxyl)ethyl]6-OMe-guanine istreated with 5-nitrofurfuryl alcohol, ByBOP, diisopropylethylamine, andN,N-dimethylformamide for 18 hours at room temperature as illustratedbelow.

Example 39 Synthesis of9-[2-(benzyloxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl]guanine

The compound9-[2-(benzyloxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl]guanine issynthesized as illustrated below.

Example 40 Synthesis of9-[2-(benzyloxy-(ethoxy-L-alanyl)-phosphonomethoxyl)ethyl]guanine

The compound9-[2-(benzyloxy-(ethoxy-L-alanyl)-phosphonomethoxyl)ethyl]guanine issynthesized as illustrated below.

Example 41 Synthesis of9-[2-(benzyloxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl]6-OMe guanine

The compound9-[2-(phenoxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl]6-OMe guanine issynthesized as illustrated below.

Example 42 Synthesis of9-[2-(benzyloxy-(ethoxy-L-alanyl)-phosphonomethoxyl)ethyl]6-OMe guanine

The compound9-[2-(phenoxy-(benzyloxy-L-alanyl)-phosphonomethoxyl)ethyl]6-OMe guanineis synthesized as illustrated below.

EMBODIMENTS

Embodiments of the compositions and methods disclosed herein include thefollowing.

Embodiment P1

Use of a compound of Formula (I), or a pharmaceutically acceptable saltthereof, in the preparation of a medicine for ameliorating or treating ahuman papillomavirus. wherein the compound of Formula (I) has thestructure:

wherein: B¹ is

and Z² are independently —O— or —NR^(Z)—, wherein R^(Z) is H or anoptionally substituted C₁₋₄ alkyl; R¹ is selected from the groupconsisting of absent, H, an optionally substituted —C₁₋₂₄ alkyl, anoptionally substituted —C₂₋₂₄ alkenyl, an optionally substituted—(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionally substituted —(CHR⁴)_(b)—O—C₂₋₂₄alkenyl, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl), an optionally substituted heteroaryl, an optionallysubstituted heterocyclyl,

R² is selected from the group consisting of an optionally substituted—C₁₋₂₄ alkyl, an optionally substituted —C₂₋₂₄ alkenyl, an optionallysubstituted —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionally substituted—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted aryl, anoptionally substituted aryl(C₁₋₄ alkyl),

or Z¹ and Z² are O; and R¹ and R² are taken together to form a moietyselected from the group consisting of an optionally substituted

and an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system; R³ is an unsubstituted C₁₋₆alkyl or an unsubstituted C₃₋₆ cycloalkyl; each R⁴ is independently H,—(CH₂)_(c)—S—C₁₋₂₄ alkyl or —O—(CH₂)_(d)—R^(4A); each R^(4A) is H, anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl;each R⁵, each R⁶ and each R⁸ are independently an optionally substitutedC₁₋₈ alkyl, an optionally substituted C₂₋₈ alkenyl, an optionallysubstituted cycloalkyl or an optionally substituted aryl; each R⁷ isindependently H, an optionally substituted C₁₋₈ alkyl, an optionallysubstituted cycloalkyl or an optionally substituted aryl; each R⁹ isindependently H or an optionally substituted C₁₋₆ alkyl; each R¹⁰ isindependently selected from the group consisting of H, an unsubstitutedC₁₋₆ alkyl, —CH₂SH, —CH₂CH₂C—(C═O)NH₂, —CH₂CH₂S CH₃, CH₂— an optionallysubstituted phenyl, —CH₂OH, —CH(OH)CH₃,

—CH₂C—(C═O)OH, —CH₂CH₂C(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; each R¹¹ is independently H, an optionally substitutedC₁₋₈alkyl, an optionally substituted cycloalkyl, an optionallysubstituted aryl or an optionally substituted aryl(C₁₋₆ alkyl); each aand each b are independently 1, 2, 3 or 4; each c and each d areindependently 0, 1, 2 or 3; provided that when R¹ is—(CH₂)₂—O—(CH₂)₁₇CH₃, then Z² cannot be O and R² cannot be anunsubstituted phenyl; and provided that when R is absent, then Z¹ is O⁻;and wherein the human papillomavirus is ameliorated or treated byinhibiting viral replication by inhibiting the synthesis of viral DNA.

Embodiment P2

A compound of Formula (I), or a pharmaceutically acceptable saltthereof, for use in ameliorating or treating a human papillomavirus,wherein the compound of Formula (I) has the structure:

(I) wherein: B¹ is

Z¹ and Z² are independently —O— or —NR^(Z)—, wherein R^(Z) is H or anoptionally substituted C₁₋₄ alkyl; R¹ is selected from the groupconsisting of absent, H, an optionally substituted —C₁₋₂₄ alkyl, anoptionally substituted —C₂₋₂₄ alkenyl, an optionally substituted—(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionally substituted —(CHR⁴)_(b)—O—C₂₋₂₄alkenyl, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl), an optionally substituted heteroaryl, an optionallysubstituted heterocyclyl,

R² is selected from the group consisting of an optionally substituted—C₁₋₂₄ alkyl, an optionally substituted —C₂₋₂₄ alkenyl, an optionallysubstituted —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionally substituted—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted aryl, anoptionally substituted aryl(C₁₋₄ alkyl),

or Z¹ and Z² are O; and R¹ and R² are taken together to form a moietyselected from the group consisting of an optionally substituted

and an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system; R³ is an unsubstituted C₁₋₆alkyl or an unsubstituted C₃₋₆ cycloalkyl; each R⁴ is independently H,—(CH₂)_(c)—S—C₁₋₂₄ alkyl or —O—(CH₂)_(d)—R^(4A); each R^(4A) is H, anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl;each R⁵, each R⁶ and each R⁸ are independently an optionally substitutedC₁₋₈ alkyl, an optionally substituted C₂₋₈ alkenyl, an optionallysubstituted cycloalkyl or an optionally substituted aryl; each R⁷ isindependently H, an optionally substituted C₁₋₈ alkyl, an optionallysubstituted cycloalkyl or an optionally substituted aryl; each R⁹ isindependently H or an optionally substituted C₁₋₆ alkyl; each R¹⁰ isindependently selected from the group consisting of H, an unsubstitutedC₁₋₆ alkyl, —CH₂SH, —CH₂CH₂C—(C═O)NH₂, —CH₂CH₂S CH₃, CH₂— an optionallysubstituted phenyl, —CH₂OH, —CH(OH)CH₃,

—CH₂C—(C═O)OH, —CH₂CH₂C(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; each R¹¹ is independently H, an optionally substitutedC₁₋₈alkyl, an optionally substituted cycloalkyl, an optionallysubstituted aryl or an optionally substituted aryl(C₁₋₆ alkyl); each aand each b are independently 1, 2, 3 or 4; each c and each d areindependently 0, 1, 2 or 3; provided that when R¹ is—(CH₂)₂—O—(CH₂)₁₇CH₃, then Z² cannot be O and R² cannot be anunsubstituted phenyl; and provided that when R¹ is absent, then Z¹ isO⁻; and wherein the human papillomavirus is ameliorated or treated byinhibiting viral replication by inhibiting the synthesis of viral DNA.

Embodiment P3

A method of ameliorating or treating a human papillomavirus comprisingcontacting a cell infected with the human papillomavirus an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein the compound of Formula (I) has the structure:

wherein: B¹ is

Z¹ and Z² are independently —O— or —NR^(Z)—, wherein R^(Z) is H or anoptionally substituted C₁₋₄ alkyl; R¹ is selected from the groupconsisting of absent, H, an optionally substituted —C₁₋₂₄ alkyl, anoptionally substituted —C₂₋₂₄ alkenyl, an optionally substituted—(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionally substituted —(CHR⁴)_(b)—O—C₂₋₂₄alkenyl, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl), an optionally substituted heteroaryl, an optionallysubstituted heterocyclyl,

R² is selected from the group consisting of an optionally substituted—C₁₋₂₄ alkyl, an optionally substituted —C₂₋₂₄ alkenyl, an optionallysubstituted —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionally substituted—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted aryl, anoptionally substituted aryl(C₁₋₄ alkyl),

or Z¹ and Z² are O; and R¹ and R² are taken together to form a moietyselected from the group consisting of an optionally substituted

and an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system; R³ is an unsubstituted C₁₋₆alkyl or an unsubstituted C₃₋₆ cycloalkyl; each R⁴ is independently H,—(CH₂)_(c)—S—C₁₋₂₄ alkyl or —O—(CH₂)_(d)—R^(4A); each R^(4A) is H, anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl;each R⁵, each R⁶ and each R⁸ are independently an optionally substitutedC₁₋₈ alkyl, an optionally substituted C₂₋₈ alkenyl, an optionallysubstituted cycloalkyl or an optionally substituted aryl; each R⁷ isindependently H, an optionally substituted C₁₋₈ alkyl, an optionallysubstituted cycloalkyl or an optionally substituted aryl; each R⁹ isindependently H or an optionally substituted C₁₋₆ alkyl; each R¹⁰ isindependently selected from the group consisting of H, an unsubstitutedC₁₋₆ alkyl, —CH₂SH, —CH₂CH₂C—(C═O)NH₂, —CH₂CH₂S CH₃, CH₂— an optionallysubstituted phenyl, —CH₂OH, —CH(OH)CH₃,

—CH₂C—(C═O)OH, —CH₂CH₂C(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; each R¹¹ is independently H, an optionally substitutedC₁₋₈ alkyl, an optionally substituted cycloalkyl, an optionallysubstituted aryl or an optionally substituted aryl(C₁₋₆ alkyl); each aand each b are independently 1, 2, 3 or 4; each c and each d areindependently 0, 1, 2 or 3; provided that when R¹ is—(CH₂)₂—O—(CH₂)₁₇CH₃, then Z² cannot be O and R² cannot be anunsubstituted phenyl; and provided that when R¹ is absent, then Z¹ isO⁻; and wherein the human papillomavirus is ameliorated or treated byinhibiting viral replication by inhibiting the synthesis of viral DNA.

Embodiment P4

A method of ameliorating or treating a human papillomavirus comprisingadministering to a subject infected with the human papillomavirus aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein the compound of Formula (I) has thestructure:

wherein: B¹ is

Z¹ and Z² are independently —O— or —NR^(Z)—, wherein R^(Z) is H or anoptionally substituted C₁₋₄ alkyl; R¹ is selected from the groupconsisting of absent, H, an optionally substituted —C₁₋₂₄ alkyl, anoptionally substituted —C₂₋₂₄ alkenyl, an optionally substituted—(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionally substituted —(CHR⁴)_(b)—O—C₂₋₂₄alkenyl, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl), an optionally substituted heteroaryl, an optionallysubstituted heterocyclyl,

R² is selected from the group consisting of an optionally substituted—C₁₋₂₄ alkyl, an optionally substituted —C₂₋₂₄ alkenyl, an optionallysubstituted —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionally substituted—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted aryl, anoptionally substituted aryl(C₁₋₄ alkyl),

or Z¹ and Z² are O; and R¹ and R² are taken together to form a moietyselected from the group consisting of an optionally substituted

and an optionally substituted

wherein Z², R¹ and R², the phosphorus and the moiety form a six-memberedto ten-membered ring system; R³ is an unsubstituted C₁₋₆ alkyl or anunsubstituted C₃₋₆ cycloalkyl; each R⁴ is independently H,—(CH₂)_(c)—S—C₁₋₂₄ alkyl or —O—(CH₂)_(d)—R^(4A); each R^(4A) is H, anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl;each R⁵, each R⁶ and each R⁸ are independently an optionally substitutedC₁₋₈ alkyl, an optionally substituted C₂₋₈ alkenyl, an optionallysubstituted cycloalkyl or an optionally substituted aryl; each R⁷ isindependently H, an optionally substituted C₁₋₈ alkyl, an optionallysubstituted cycloalkyl or an optionally substituted aryl; each R⁹ isindependently H or an optionally substituted C₁₋₆ alkyl, each R¹⁰ isindependently selected from the group consisting of H, an unsubstitutedC₁₋₆ alkyl, —CH₂SH, —CH₂CH₂C—(C═O)NH₂, —CH₂CH₂S CH₃, CH₂— an optionallysubstituted phenyl, —CH₂OH, —CH(OH)CH₃,

—CH₂C—(C═O)OH, —CH₂CH₂C(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; each R¹¹ is independently H, an optionally substitutedC₁₋₈ alkyl, an optionally substituted cycloalkyl, an optionallysubstituted aryl or an optionally substituted aryl(C₁₋₆ alkyl); each aand each b are independently 1, 2, 3 or 4; each c and each d areindependently 0, 1, 2 or 3; provided that when R¹ is—(CH₂)₂—O—(CH₂)₁₇CH₃, then Z² cannot be O and R² cannot be anunsubstituted phenyl; and provided that when R¹ is absent, then Z¹ isO⁻; and wherein the human papillomavirus is ameliorated or treated byinhibiting viral replication by inhibiting the synthesis of viral DNA.

Embodiment P5

The use of Embodiment P1, the compound of Embodiment P2, or the methodof Embodiment P3 or P4, wherein the human papillomavirus is a high-riskhuman papillomavirus.

Embodiment P6

The use, compound or method of Embodiment P5, wherein the humanpapillomavirus is selected from the group consisting of HPV-16, HPV-18,HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58,HPV-59, HPV-68, HPV-73, and HPV-82.

Embodiment P7

The use, compound or method of Embodiment P5, wherein the humanpapillomavirus is HPV-16.

Embodiment P8

The use, compound or method of Embodiment P5, wherein the humanpapillomavirus is HPV-18.

Embodiment P9

The use of Embodiment P1, the compound of Embodiment P2, or the methodof Embodiment P3 or P4, wherein the human papillomavirus is a low-riskhuman papillomavirus.

Embodiment P10

The use, compound or method of Embodiment P9, wherein the humanpapillomavirus is HPV-6.

Embodiment P11

The use, compound or method of Embodiment P9, wherein the humanpapillomavirus is HPV-11.

Embodiment P12

The use, compound or method of any one of Embodiments P1-P11, wherein R¹is absent or H; and R² is selected from the group consisting of anoptionally substituted —C₁₋₂₄ alkyl, an optionally substituted —C₂₋₂₄alkenyl, an optionally substituted —(CHR¹)_(a)—O—C₁₋₂₄ alkyl, anoptionally substituted —(CHR¹)_(b)—O—C₂₋₂₄ alkenyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl),

Embodiment P13

The use, compound or method of Embodiment P12, wherein R¹ is absent orH; and R² is an optionally substituted —(CHR¹)_(a)—O—C₁₋₂₄ alkyl or anoptionally substituted —(CHR¹)_(b)—O—C₂₋₂₄ alkenyl.

Embodiment P14

The use, compound or method of Embodiment P12, wherein R¹ is absent orH; and R² is an optionally substituted —C₁₋₂₄ alkyl or an optionallysubstituted —C₂₋₂₄ alkenyl.

Embodiment P15

The use, compound or method of Embodiment P12, wherein R¹ is absent orH; and R² is an optionally substituted aryl.

Embodiment P16

The use, compound or method of Embodiment P12, wherein R¹ is absent orH; and R² is an optionally substituted aryl(C₁₋₄ alkyl).

Embodiment P17

The use, compound or method of Embodiment P12, wherein R¹ is absent orH; and R² is

Embodiment P18

The use, compound or method of Embodiment P12, wherein R¹ is absent orH; and R² is

Embodiment P19

The use, compound or method of Embodiment P12, wherein R¹ is absent orH; and R² is

Embodiment P20

The use, compound or method of Embodiment P12, wherein R¹ is absent orH; and R² is

Embodiment P21

The use, compound or method of Embodiment P12, wherein R¹ is absent orH; and R² is

Embodiment P22

The use, compound or method of any one of Embodiments P1-P11, wherein R¹and R² are independently selected from the group consisting of anoptionally substituted —C₁₋₂₄ alkyl, an optionally substituted —C₂₋₂₄alkenyl, an optionally substituted —(CHR¹)_(a)—O—C₁₋₂₄ alkyl, anoptionally substituted —(CHR¹)_(b)—O—C₂₋₂₄ alkenyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl),

Embodiment P23

The use, compound or method of Embodiment P22, wherein R¹ and R² areindependently an optionally substituted —(CHR¹)_(a)—O—C₁₋₂₄ alkyl or anoptionally substituted —(CHR¹)_(b)—O—C₂₋₂₄ alkenyl.

Embodiment P24

The use, compound or method of Embodiment P22, wherein R¹ and R² areindependently an optionally substituted —C₁₋₂₄ alkyl or an optionallysubstituted —C₂₋₂₄ alkenyl.

Embodiment P25

The use, compound or method of Embodiment P22, wherein R¹ and R² areindependently an optionally substituted aryl.

Embodiment P26

The use, compound or method of Embodiment P22, wherein R¹ and R² areindependently an optionally substituted aryl(C₁₋₄ alkyl).

Embodiment P7

The use, compound or method of Embodiment P22, wherein R¹ and R² areindependently

Embodiment P28

The use, compound or method of Embodiment P22, wherein R¹ and R² areindependently

Embodiment P29

The use, compound or method of Embodiment P22, wherein R¹ and R² are

Embodiment P30

The use, compound or method of Embodiment P22, wherein R¹ and R² areindependently

Embodiment P31

The use, compound or method of Embodiment P22, wherein R¹ is

and R² is an optionally substituted —C₁₋₂₄ alkyl.

Embodiment P32

The use, compound or method of any one of Embodiments P1-P31, wherein Z¹is O.

Embodiment P33

The use, compound or method of any one of Embodiments P1-P31, wherein Z¹is NH.

Embodiment P34

The use, compound or method of any one of Embodiments P1-P31, wherein Z¹is N-optionally substituted C₁₋₄ alkyl.

Embodiment P35

The use, compound or method of any one of Embodiments P1-P34, wherein Z²is O.

Embodiment P36

The use, compound or method of any one of Embodiments P1-P34, wherein Z²is NH.

Embodiment P37

The use, compound or method of any one of Embodiments P1-P34, wherein Z²is N-optionally substituted C₁₋₄ alkyl.

Embodiment P38

The use, compound or method of any one of Embodiments P1-P11, wherein Z¹and Z² are O; and R¹ and R² are taken together to form a moiety selectedfrom the group consisting of an optionally substituted

and an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system.

Embodiment P39

The use, compound or method of any one of Embodiments P1-P38, wherein B¹is

Embodiment P40

The use, compound or method of any one of Embodiments P1-P38, wherein B¹is

Embodiment P41

The use, compound or method of any one of Embodiments P1-P11, whereinthe compound is selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.

Further embodiments of the compositions and methods disclosed hereinfollow.

Embodiment 1

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 2

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 3

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 4

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 5

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 6

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 7

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 8

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 9

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 10

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 11

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 12

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 13

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 14

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 15

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 16

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof

Embodiment 17

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof

Embodiment 18

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof

Embodiment 19

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 20

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof

Embodiment 21

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof

Embodiment 22

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof

Embodiment 23

A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Embodiment 24

A compound selected from the group consisting of:

wherein R^(M) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carb amyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group; and the phenyl ring can be substituted byR^(M) 1, 2 or 3 times; or a pharmaceutically acceptable salt thereof.

Embodiment 25

A compound selected from the group consisting of:

wherein R^(M) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carb amyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group; and the phenyl ring can be substituted byR^(M) 1, 2 or 3 times; or a pharmaceutically acceptable salt thereof.

Embodiment 26

A compound selected from the group consisting of:

wherein R^(M) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group; and the phenyl ring can be substituted byR^(M) 1, 2 or 3 times; or a pharmaceutically acceptable salt thereof.

Embodiment 27

A pharmaceutical composition, comprising an effective amount of acompound of any of embodiments 1-26, in a pharmaceutically acceptablecarrier.

Embodiment 28

The pharmaceutical composition of embodiment 27, wherein the compositionis suitable for topical delivery.

Embodiment 29

A method of treating a host infected with a human papillomavirus,comprising administering an effective amount of a compound of any ofembodiments 1-28, or a pharmaceutically acceptable salt thereof,optionally in a pharmaceutically acceptable carrier.

Embodiment 30

A method of treating a host infected with a human papillomavirus,comprising administering an effective amount of a compound of any ofembodiments 1-28, or a pharmaceutically acceptable salt thereof,optionally in a pharmaceutically acceptable carrier, wherein the humanpapillomavirus is a high-risk human papillomavirus.

Embodiment 31

The method of embodiment 30, wherein the human papillomavirus isselected from the group consisting of HPV-16, HPV-18, HPV-31, HPV-33,HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68,HPV-73, and HPV-82.

Embodiment 32

The method of embodiment 30, wherein the human papillomavirus is HPV-16.

Embodiment 33

The method of embodiment 30, wherein the human papillomavirus is HPV-18.

Embodiment 34

The method of any of embodiment 29, wherein the host is a human.

Embodiment 35

The method of any of embodiment 30, wherein the host is a human.

Embodiment 36

The method of any of embodiment 31, wherein the host is a human.

Embodiment 37

The method of any of embodiment 32, wherein the host is a human.

Embodiment 38

Use of a compound of any of embodiments 1-28 or a pharmaceuticallyacceptable salt thereof in the manufacture of a medicament for treatmentof a papillomavirus infection.

Embodiment 39

A method for manufacturing a medicament intended for the therapeutic usefor treating a papillomavirus infection, characterized in that thecompound as described in any of embodiments 1-28 is used in themanufacture.

Embodiment 40

Use of a compound having the structure:

or its pharmaceutically acceptable salt thereof, in the manufacture of amedicament for treatment of a papillomavirus infection.

Embodiment 41

Use of a compound having the structure:

or its pharmaceutically acceptable salt thereof, in the manufacture of amedicament for treatment of a papillomavirus infection.

Although the foregoing has been described in some detail by way ofillustrations and examples for purposes of clarity and understanding, itwill be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present disclosure. Therefore, it should be clearly understood thatthe forms disclosed herein are illustrative only and are not intended tolimit the scope of the present disclosure, but rather to also cover allmodification and alternatives coming with the true scope and spirit ofthe disclosure.

1.-25. (canceled)
 26. A compound selected from the group consisting of:


27. The compound of claim 26 with structure:


28. The compound of claim 26 with structure:


29. The compound of claim 26 with structure:


30. The compound of claim 26 with structure:


31. The compound of claim 26 with structure:


32. The compound of claim 26 with structure:


33. The compound of claim 26 with structure:


34. The compound of claim 26 with structure:


35. The compound of claim 26 with structure:


36. The compound of claim 26 with structure: